WO2015191686A1 - Methods of administering methylnaltrexone - Google Patents

Abstract

Provided herein are methods of decreasing the risk of a cardiovascular event in a subject having opioid induced constipation, comprising administering to the subject a pharmaceutical composition comprising methylnaltrexone. Also provided herein are methods of increasing compliance with opioid treatment in a subject having opioid induced constipation, wherein the methods comprise administration of a pharmaceutical composition comprising methylnaltrexone. Embodiments are also directed to methods of treating opioid constipation in subjects with hepatic or renal impairment, wherein the methods comprise administration of a pharmaceutical composition comprising methylnaltrexone.

Description

METHODS OF ADMINISTERING METHYLNALTREXONE Related Applications

This application claims the benefit of U.S. Provisional Application No. 62/010,415, filed on June 10, 2014, U.S. Provisional Application No. 62/010,997, filed on June 11, 2014 and U.S. Provisional Application No. 62/011,007, filed on June 11, 2014, the entirety of each of which are incorporated by reference.

Background

Opioids are widely used in treating patients with pain. Such patients include those with advanced cancers and other terminal diseases and also those with chronic non-malignant pain and acute non-malignant pain. Opioids are narcotic medications that activate opioid receptors located in the central nervous system to relieve pain. Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and severe itching. Notable are the effects of opioids in the gastrointestinal (GI) tract where these drugs inhibit gastric emptying and peristalsis in the intestines, thereby decreasing the rate of intestinal transit and producing constipation. The use of opioids in treating pain is often limited due to these undesired side effects, which can be debilitating and often cause patients to refuse the use of opioid analgesics.

In addition to exogenous opioid-induced side effects, studies have suggested that endogenous opioids and opioid receptors can also affect the gastrointestinal (GI) tract and can be involved in normal regulation of intestinal motility and mucosal transport of fluids. Thus, an abnormal physiological level of endogenous opioids and/or receptor activity can also lead to bowel dysfunction. For example, patients who have undergone surgical procedures, especially surgery of the abdomen, often suffer from a particular bowel dysfunction, termed post-operative ileus, that can be caused by fluctuations in natural opioid levels. Similarly, women who have recently given birth commonly suffer from post partum ileus, which can be caused by similar fluctuations in natural opioid levels as a result of birthing stress. Gastrointestinal dysfunction associated with post-operative or post-partum ileus can typically last for 3 to 5 days, with some severe cases lasting more than a week. Administration of opioids to a patient after surgery to treat pain, which is now an almost universal practice, can exacerbate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing medical care costs. Opioid receptor antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the undesirable peripheral side effects of opioids. However, these agents not only act on peripheral opioid receptors but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing symptoms of opioid withdrawal. Preferable approaches for use in controlling opioid-induced side effects include administration of peripheral acting opioid receptor antagonists that do not readily cross the blood-brain barrier.

The peripheral μ opioid receptor antagonist methylnaltrexone has been studied since the late 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention(see, e.g., U.S. Patents 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al, Drug and Alcohol Dependence 1998, 52, 161). The dosage form of methylnaltrexone used most often in these studies has been a solution of methylnaltrexone for intravenous injection.

Summary

Provided herein are methods of treating opioid-induced constipation in a subject, wherein the method decreases the risk of a cardiovascular event in a subject having opioid induced constipation, wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II):

II wherein A^" is a suitable anion, and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of a cardiovascular event in the subject.

Also disclosed herein are methods of decreasing the risk of a a cardiovascular event in a subject having opioid induced constipation, wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A^" is a suitable anion, and wherein the administration of the pharmaceutical composition reduces the risk of a cardiovascular event in the subject. In some embodiments, administration of the pharmaceutical composition results in a rescue free bowel movement and/or improved stool consistency, thereby reducing the risk of a cardiovascular event in the subject.

In one embodiment, the risk of a cardiovascular event in the subject is reduced due to a reduction in straining.

In one embodiment, the risk of a cardiovascular event in the subject is reduced due to the subject's ability to maintain optimal opioid pain management.

In one embodiment, the cardiovascular event is at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.

In one embodiment, the cardiovascular event is at least one selected from the group of: elevated pulse, stroke, changes in blood pressure, changes in systolic blood pressure and changes in diastolic blood pressure.

Embodiments are also directed to methods of increasing compliance with opioid treatment in a subject having opioid induced constipation, wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A^" is a suitable anion, and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of symptoms of opioid withdrawal.

Embodiments also relate to methods of treating opioid-induced constipation in a subject, wherein the methods include: administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A^" comprises a suitable anion, and wherein the subject is suffering from hepatic impairment. In one embodiment, the subject has Child-Pugh Class B or Class C hepatic impairment.

Also provided herein are methods of treating opioid-induced constipation in a subject, wherein the methods include: administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A^" comprises a suitable anion, and wherein the subject is suffering from renal impairment. In one embodiment, the subject has a renal clearance rate of C1R = 52 + 28 mL/min. In one embodiment, the subject has a creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault.

In one embodiment, the subject has advanced illness and is receiving palliative care. In one embodiment, the subject's response to laxative therapy has not been sufficient. In one embodiment, the subject has advanced chronic pain.

In one embodiment, the subject's response to laxative therapy has not been sufficient.

In one embodiment, the method increases compliance with opioid treatment in a subject having opioid induced constipation.

In one embodiment, the subject thereby reduces the risk of opioid withdrawal. In one embodiment, the risk of opioid withdrawal includes risk of having one or more withdrawal symptoms. In one embodiment, the subject thereby reduces the risk of having one or more withdrawal symptoms.

In one embodiment, the subject is also administered opioids. In one embodiment, the administering of the pharmaceutical composition comprising a compound of formula (II) is not followed by an adjustment of administration of the opioid in the subject. In one embodiment, the administering of the pharmaceutical composition does not lead to an adjustment of the dosage of opioid administered to the subject. In one embodiment, the administering of the pharmaceutical composition is not followed by an increase in the dosage of the opioid administered to the subject.

In one embodiment, the administering of the pharmaceutical composition is not followed by an increase in pain intensity experienced by the subject.

Presented herein are methods of treating opioid-induced constipation in a subject, wherein the method decreases the risk of a cardiovascular event in a subject having opioid induced constipation, comprising: administering to the subject a pharmaceutical composition comprising one or more peripherally- acting mu-opioid receptor antagonists (PAMORA), and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of a cardiovascular event in the subject.

In one embodiment, A^" includes an anion selected from the group consisting of: chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt. In one embodiment, A^" includes bromide.

In one embodiment, A^" includes an anion selected from the group consisting of: is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulphate. In one embodiment, A^" includes bromide and dodecyl (lauryl) sulfate.

In one embodiment, the pharmaceutical composition further includes at least one agent selected from the group consisting of sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof.

In one embodiment, the pharmaceutical composition further includes at least one agent selected from the group consisting of colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscarmellose sodium, poloxamer 407, siliconized microcrystalline cellulose, stearic acid.and combinations thereof.

In one embodiment, the pharmaceutical composition dosage form is a tablet.

In one embodiment, administration includes orally administering from about 150 mg to about 450 mg of methylnaltrexone, or a salt thereof. In one embodiment, administration includes orally administering about 150 mg, about 300 mg, or about 450 mg of methylnaltrexone, or a salt thereof. In one embodiment, the methylnaltrexone is administered as one or more tablets, wherein each tablet contains about 150 mg of methylnaltrexone.

In one embodiment, the subject has chronic non-malignant pain. In one embodiment, the subject has had chronic non-malignant pain for at least 2 months prior to administration of the pharmaceutical composition.

In one embodiment, the subject has been receiving opioid treatment prior to administration of the pharmaceutical composition. In one embodiment, the subject has been receiving opioid treatment for at least one month. In one embodiment, the subject has been receiving opioid treatment comprising at least 50 mg of oral morphine equivalents per day for at least 14 days.

In one embodiment, the subject will start opioid treatment in less than 1, 2, 3 or 4 weeks.

In one embodiment, the subject has had opioid induced constipation for at least 30 days.

In one embodiment, the subject has experienced less than 3 rescue free bowel movements per week for at least four consecutive weeks.

In one embodiment, the subject has experienced straining during bowel movements.

In one embodiment, the administering results in a rescue free bowel movement within 4 hours of administration of the pharmaceutical composition. In one embodiment, the administering results in an increase of at least one rescue free bowel movement per week as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.

In one embodiment, the administering results in an increase of at least 2, 3, 4 or 5 rescue free bowel movements per week.

In one embodiment, the administering results in an increase of at least one rescue free bowel movement per week for each of the first 4 weeks of daily administration of the pharmaceutical composition.

In one embodiment, the administering results in improved stool consistency.

In one embodiment, the subject experiences at least 3 rescue free bowel movements in each of the first 4 weeks of daily administration of the pharmaceutical composition; and the subject experiences an increase of at least one rescue free bowel movement per week for at least 3 of the first 4 weeks of daily administration as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.

In some embodiments, the administering comprises orally administering about 150 mg of methylnaltrexone, or a salt thereof.

In some embodiments, the administering comprises orally administering about 300 mg of methylnaltrexone, or a salt thereof.

In some embodiments, the administering comprises orally administering less than about 450 mg of methylnaltrexone, or a salt thereof.

In some embodiments, administration of the pharmaceutical composition does not result in any clinically significant drug-drug interactions.

In some embodiments, administration of the pharmaceutical composition demonstrates minimal interaction with CYP enzymes and/or drug transporters.

Other embodiments are disclosed infra.

Brief Description of the Drawings

Figure 1 summarizes adverse events that occurred amongst all subjects as set forth in Example 1.

Figure 2 summarizes serious adverse events by system organ class that occurred amongst all subjects as set forth in Example 1.

Figure 3 summarizes adverse events by system organ class that occurred amongst all subjects as set forth in Example 1. Figure 4 summarizes clinically significant ECG results as set forth in Example 1.

Figure 5 includes charts that illustrate that straining and stool consistency improved as a result of administration of methylnaltrexone during an open label study of the drug.

Figure 6 includes charts that illustrate the sustainability of rapid response and durability of efficacy of administration of methylnaltrexone during an open label study of the drug.

Figure 7 is a table summarizing mean pulse (beats per minute) and supine blood pressure (mm Hg) changes from baseline on Day 1 and Day 3 in post-operative ileus studies involving administration of methylnaltrexone.

Figure 8 is a table summarizing outliers for pulse and blood pressure parameters over 10 days of observation in the same post-operative ileus studies.

Figure 9 is a series of charts illustrating that there was no consistent, clinically meaningful changes in supine pulse or blood pressure among subjects with opioid-induced constipation and chronic non-cancer pain who were administered methylnaltrexone.

Figure 10 is a table illustrating the lack of metabolic effects observed over a 48-week period of time in subjects having chronic non-cancer pain and opioid-induced constipation who were administered methylnaltrexone (12 mg PRN).

Figure 11 is a table summarizing the comparable event rates for myocardial infarction among subjects having chronic non-cancer pain and chronic opioid use.

Figure 12 is a table that summarizes cardiac adverse events between placebo and treatment groups for methylnaltrexone.

Figure 13 is a graph that summarizes changes in the pulse of subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone.

Figure 14 is a graph that summarizes changes in Systolic Blood Pressure in subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone .

Figure 15 is a graph that summarizes changes in Diastolic Blood Pressure in subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone .

Figure 16 is a graph is a graph that summarizes changes in pulse in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone. Figure 17 is a graph is a graph that summarizes changes in Systolic Blood Pressure in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone .

Figure 18 is a graph that summarizes changes in Diastolic Blood Pressure in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone .

Figure 19 is a graph that summarized all-cause mortality in Placebo controlled study of Relistor.

Figure 20 is a graph that summarizes the timing of reported Myocardial Infarctions in Placebo controlled study of Relistor as compared to a placebo controlled study of Alvimopan.

Figure 21 is a table that summarizes the incidence of potential opioid withdrawal symptoms.

Figure 22 is a table that summarizes the assessment of opioid withdrawal.

Figure 23 is a table that summarizes the assessment of opioid withdrawal.

Figure 24 demonstrates the rapid and durable efficacy of Relistor.

Figure 25 shows in vitro inhibition of platelet aggregation in naloxone, naltrexone, methylnaltrexone and alvimopan.

Figure 26 summarizes pain intensity reported by patients.

Figure 27 is a bar chart illustrating an efficacy endpoint after a single dose of oral methylnaltrexone (two separate formulations) relative to placebo.

Figure 28 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone following a single oral dose of methylnaltrexone in subjects.

Figure 29 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M2 (methylnaltrexone sulfate) following a single oral dose of methylnaltrexone in subjects.

Figure 30 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M4 (methyl-6a-naltrexol) following a single oral dose of methylnaltrexone in subjects.

Figure 31 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M5 (methyl-6b-naltrexol) following a single oral dose of methylnaltrexone in subjects.

Figure 32 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone following a single oral dose of methylnaltrexone in subjects. Figure 33 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M2 (methylnaltrexone sulfate) following a single oral dose of methylnaltrexone in subjects.

Figure 34 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M4 (methyl-6a-naltrexol) following a single oral dose of methylnaltrexone in subjects.

Figure 35 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M5 (methyl-6b-naltrexol) following a single oral dose of methylnaltrexone in subjects.

Figure 36 is a plot of observed and predicted methylnaltrexone pharmacokinetic parameters correlated with a single dose of 450 mg and 150 mg (respectively) oral methylnaltrexone in healthy subjects and subjects with hepatic impairment.

Figure 37 is a plot of observed and predicted methylnaltrexone pharmacokinetic parameters correlated with a single dose of 450 mg and 300 mg (respectively) oral methylnaltrexone in healthy subjects and subjects with renal impairment.

Figure 38 is a plot of the proportion of subjects who experienced laxation within four hours after administration of methylnaltrexone versus the midpoint of each C_max quintile, analyzed across six studies.

Figure 39 is a plot showing time to laxation after administration of methylnaltrexone versus plasma MNTX C_max, analyzed across six studies.

Figure 40 is a fit of a logistic regression model to the probability of laxation within four hours of methylnaltrexone administration for various T_max values versus ln(C_max) +1 from a model development data set.

Detailed Description of Certain Embodiments of the Invention

Embodiments are directed to methods for preventing and treating the inhibition of gastrointestinal motility, particularly constipation, that arises in the group of patients taking chronic or maintenance doses of opioids, comprising administering a therapeutically effective amount of a quaternary derivative of noroxymorphone (QDNM). These patients include late stage cancer patients, elderly patients with osteoarthritic changes, methadone maintenance patients, neuropathic pain and chronic back pain patients. Treatment of these patients is important from a quality of life standpoint, as well as to reduce complications arising from chronic constipation, such as hemorrhoids, appetite suppression, mucosal breakdown, sepsis, colon cancer risk, and myocardial infarction.

In some embodiments, the quaternary derivative of noroxymorphone is methylnaltrexone. In some embodiments, the opioid-induced side effect to be treated includes, but is not limited to, constipation and gastrointestinal motility inhibition, dysphoria, pruritus, and urinary retention.

Quaternary derivatives of noroxymorphone are described in full in Goldberg et al., U.S. Pat. No. 4, 176,186, which is incorporated herein by reference in its entirety. In general, these derivatives are represented by Formula I:

I

wherein R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.

Provided herein is a method of decreasing the risk of a cardiovascular event a subject suffering from opioid-induced constipation, comprising administering a composition comprising methylnaltrexone to the subject. In some embodiments, the methylnaltrexone is administered subcutaneously. In some embodiments, the methylnaltrexone is administered orally. In some embodiments, the subject is receiving opioids chronically. In some embodiments, administration of the composition results in a decrease of about one point in a bowel movement straining scale. In some embodiments, administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale). In some embodiments, the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks. The cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias. Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including," as well as other forms of the term, such as "includes" and "included", is not limiting.

The term "constipation" as used herein, refers to a condition in which a subject suffers from infrequent bowel movements or bowel movements that are painful and/or hard to pass. A subject experiencing constipation often suffers from straining during bowel movements and/or a sensation of incomplete evacuation following bowel movements. In a particular embodiment, constipation refers to a subject who experiences less than three (3) rescue free bowel movements (RFBMs) per week on average, wherein "rescue free bowel movement" refers to the passage and evacuation of feces, or laxation.

As used herein, the term "opioid induced constipation" (OIC) refers to a subject who suffers from constipation resulting from opioid therapy. For example, a subject can suffer from opioid induced constipation arising from opioid therapy with alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and/ or tramadol.

As used herein, an "effective amount" of a composition of methylnaltrexone refers to the level required to treat or prevent one or more symptoms of opioid induced constipation. In some embodiments, an "effective amount" is at least a minimal amount of a composition of methylnaltrexone, which is sufficient for treating or preventing one or more symptoms of opioid induced constipation, as defined herein. In some embodiments, the term "effective amount," as used in connection with an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof, refers to an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof sufficient to achieve a rescue free bowel movement in a subject.

As used herein, maintain optimal opioid pain management includes, for example, not lowering the dose of opioid due to constipation.

Presented herein are methods of treating opioid-induced constipation in a subject, wherein the method decreases the risk of a cardiovascular event in a subject having opioid induced constipation, comprising: administering to the subject a pharmaceutical composition comprising one or more peripherally- acting mu-opioid receptor antagonists (PAMORA), and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of a cardiovascular event in the subject.

As used herein, peripherally- acting mu-opioid receptor antagonists (PAMORA), include for example, methylnaltrexone, naloxegol, naloxegol. PAMORA may also include centrally acting mu-opioid receptor antagonists that have been formulated to act only peripherally (e.g., formulated to reduce or eliminate their absorption or systemic availability.

The terms "treat" or "treating," as used herein, refers to partially or completely alleviating, inhibiting, delaying onset of, reducing the incidence of, ameliorating and/or relieving opioid induced constipation, or one or more symptoms of opioid induced constipation.

The expression "unit dosage form" as used herein refers to a physically discrete unit of a composition or formulation of methylnaltrexone, appropriate for the subject to be treated. It will be understood, however, that the total daily usage of provided formulation will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject will depend upon a variety of factors including the severity of the opioid induced constipation; nature and activity of the composition; specific formulation employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

As used herein, the term "non-malignant pain" refers to pain originating from a non- malignant source such as cancer.

The term "subject", as used herein, means a mammal and includes human and animal subjects, such as domesticated animals (e.g. , horses, dogs, cats, etc.) and experimental animals (e.g. , mice, rats, dogs, chimpanzees, apes, etc.). In a particular embodiment, the subject is human.

The terms "suffer" or "suffering" as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have, in particular, opioid induced constipation.

The term "amphiphilic" as used herein to describe a molecule refers to the molecule's dual hydrophobic and hydrophilic properties. Typically, amphiphilic molecules have a polar, water soluble group (e.g. , a phosphate, carboxylic acid, sulfate) attached to a nonpolar, water- insoluble group (e.g., a hydrocarbon). The term amphiphilic is synonymous with amphipathic. Examples of amphiphilic molecules include sodium dodecyl (lauryl) sulfate, fatty acids, phospholipids, and bile acids. Amphiphilic molecules can be uncharged, cationic, or anionic.

As used herein, the term "liphophilicity" refers to a compound' s ability to associate with or dissolve in a fat, lipid, oil, or non-polar solvent. Lipophilicity and hydrophobicity can be used to describe the same tendency of a molecule to dissolve in fats, oils, lipids, and non- polar solvents.

As used herein, "Relistor" or "Relistor®" is used to indicate methylnaltrexone.

In embodiments wherein the subject' s response to laxative therapy has not been sufficient, this can refer to the lack of a bowel movement or adequate relief from constipation within about 48 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 12 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 6 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 4 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 2 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 1 hour after administration of laxative therapy. Provided herein are compositions comprising a compound of formula II and/or II'

II ΙΓ

wherein A^" is a suitable anion.

In some embodiments, A^" is the anion of a suitable Br0nsted acid. Exemplary Br0nsted acids include, but are not limited to, hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid and phosphoric acid. In some embodiments, A^" is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt. In some embodiments, A^" is trifluoroacetate. In some embodiments, A^" is bromide.

In some embodiments, compositions comprising are formulated in a liquid formulation. Liquid formulations and compositions of methylnaltrexone are described, for example, in International Publications No. WO 2004/091623, WO 2008/019115 and WO 2010/039851, each of which is incorporated herein by reference in its entirety. In some embodiments, the liquid formulation or composition is provided in a packaged composition that is substantially free of tungsten, as described, for example in WO 2010/039851. For example, a packaged composition that is substantially free from tungsten can be provided, comprising a unit dosage of a liquid composition comprising methylnaltrexone, a calcium chelating agent, a buffering agent and an isotonicity agent. In some embodiments, the packaged composition can comprise a unit dosage of a liquid composition that comprises methylnaltrexone bromide, edetate calcium disodium and glycine hydrochloride. In some embodiments, the packaged composition can comprise a unit dosage of a liquid composition that comprises methylnaltrexone bromide, edetate calcium disodium and glycine hydrochloride and sodium chloride.

In some embodiments, the liquid formulation or composition comprises a compound of Formula II and/or II'.

A packaged composition can include, for example, vials, ampoules, prefilled syringes or sachets containing liquids. In some embodiments, the liquid composition comprising methylnaltrexone has a pH of from about pH 2.0 to about pH 6.0. In some embodiments, the pH of the formulation is from about pH 2.6 to about pH 5.0. In some embodiments, the pH of the formulation is from about pH 3.0 to about pH 4.0. In some embodiments, the pH of the formulation is from about pH 3.4 to about pH 3.6. In some embodiments, the pH of the formulation is about pH 3.5.

In some embodiments, the liquid composition comprising methylnaltrexone has a pH of from about pH 2.5 to about pH 6.0.

In some embodiments, the packaged composition comprises methylnaltrexone in an amount from about 0.5 mg to about 200 mg, about 1 mg to about 80 mg, from about 5 mg to about 40 mg. In some embodiments, the packaged composition comprises methylnaltrexone bromide in an amount of about 8 mg, about 12 mg, about 16 mg, about 18 mg, or about 24 mg.

In some embodiments, the packaged composition comprises a liquid composition comprising methylnaltrexone bromide in an amount from about 0.01 mg/mL to about 2 mg/mL, or from about 0.1 mg/mL to about 1 mg/mL in the formulation, or from about 0.2 mg/mL to about 0.8 mg/mL of the formulation.

In some embodiments, a chelating agent can be present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the chelating agent is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.

Exemplary chelating agents include ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic acid, versene acid, and sequestrene), and EDTA derivatives, such as sodium EDTA, and potassium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts thereof. Other chelating agents include niacinamide and derivatives thereof and sodium desoxycholate and derivatives thereof, ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid (EGTA) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and derivatives thereof, N,N- bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof. Additional chelating agents that are contemplated include citric acid and derivatives thereof. Citric acid also is known as citric acid monohydrate. Derivatives of citric acid include anhydrous citric acid and trisodiumcitrate-dihydrate. In some embodiments, the chelating agent is at least one selected from the group consisting of EDTA, an EDTA derivative, EGTA and an EGTA derivative. In some embodiments, the chelating agent comprises EDTA disodium such as, for example, EDTA disodium hydrate.

In some embodiments, a calcium salt is present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the calcium salt is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.

Exemplary calcium salts include, but are not limited to calcium chloride, calcium acetate, calcium citrate, calcium sulfate, and the like.

In some embodiments, a calcium salt chelating agent is present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the calcium salt chelating agent is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.

Common calcium salt chelating agents include, but are not limited to calcium ethylenediaminetetra acetic acid (EDTA) and calcium salt EDTA derivatives, calcium ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid (EGTA) and calcium salt EGTA derivatives, calcium diethylenetriaminepentaacetic acid (DTPA) and calcium salt DTPA derivatives, calcium N,N-bis(carboxymethyl)glycine (NTA) and calcium salt NTA derivatives, and calcium citrate and derivatives thereof. In some embodiments, the calcium salt chelating agent is at least one selected from the group of calcium EDTA, a calcium salt EDTA derivative, calcium EGTA and a calcium salt EGTA derivative. In some embodiments, the calcium salt chelating agent comprises calcium EDTA disodium such as, for example, calcium EDTA disodium hydrate.

In some embodiments, an isotonic agent is present in the liquid composition. Common isotonic agents include agents selected from the group consisting of sodium chloride, mannitol, lactose, dextrose (hydrous or anhydrous), sucrose, glycerol, and sorbitol, and solutions thereof.

In some embodiments, a stabilizing agent is present in the liquid composition in an amount of from about 0.01 mg/mL to about 2 mg/mL, or from about 0.05 mg/mL to about 1 mg/mL, or from about 0.1 mg/mL to about 0.8 mg/mL. In some embodiments, the stabilizing agent can be present in an amount of about 0.10 mg/mL, about 0.15 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about 0.35 mg/mL, about 0.4 mg/mL, about 0.45 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL or about 0.8 mg/mL.

Exemplary stabilizing agents include glycine, benzoic acid, citric, glycolic, lactic, malic, and maleic acid. In some embodiments, the liquid formulation comprises glycine. In some embodiments, the glycine comprises glycine-HCl.

For intravenous or intramuscular administration, methylnaltrexone (from, e.g., Mallinckrod Pharmaceuticals, St. Louis, Mo.) can be formulated with saline or other physiologically acceptable carriers. For transmucosal administration, methylnaltrexone can be formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art.

In some embodiments, the methods presented herein involve administration of oral compositions of methylnaltrexone comprising ion pairs of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient. For example, the composition for use in the methods presented herein can be a salt of methylnaltrexone of the formula:

wherein methylnaltrexone is the cation of the salt, and A^" is an anion of an amphiphilic pharmaceutically acceptable excipient, as described in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein. In certain embodiments, the methylnaltrexone is (R)-N-methylnaltrexone, a peripherally acting μ opioid receptor antagonist, as shown in the formula above. It will be understood that the (R)-N-methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient can exist in the composition as an ion pair or can exist as separate salts paired with other counter ions such as bromide and sodium, or mixtures thereof.

In some embodiments, the methods presented herein involve administration of oral compositions of methylnaltrexone comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient. For example, the composition for use in the methods presented herein can be a compound of methylnaltrexone of the formula:

wherein A^" comprises a suitable anion. In some embodiments, A^" comprises an anion of an amphiphilic pharmaceutically acceptable excipient, as described in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein. In certain embodiments, the methylnaltrexone is (R)-N-methylnaltrexone, a peripherally acting μ opioid receptor antagonist, as shown in the formula above. It will be understood that the (R)-N-methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient can exist in the composition as an ion pair or can exist as separate salts paired with other counter ions such as bromide and sodium, or mixtures thereof.

The compositions for oral administration further include an anion of an amphiphilic pharmaceutically acceptable excipient (A ). The amphiphilic pharmaceutically acceptable excipient increases the lipophilicity of the composition thereby allowing for increased transport through the unstirred diffusion layer in the GI tract, resulting in increased permeation through biological membranes. In certain embodiments, the excipient increases the lipophilicity of the drug.

In some embodiments, the amphiphilic pharmaceutically acceptable excipient can include a sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety. In some embodiments, the pharmaceutically acceptable excipient comprises an (-OSO₃ ) group. In some embodiments, the anion is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulphate.

In some embodiments, A^" is the anion of a Br0nsted acid. Exemplary Br0nsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid. In some embodiments, A^" is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt. In some embodiments, A^" is trifluoroacetate.

In some embodiments, the methylnaltrexone in the composition can have multiple anions (e.g., bromide and dodecyl (lauryl) sulfate) associating therewith.

In some embodiments, A^" is bromide, such that the compositions, and formulations thereof, comprise (R)-N-methylnaltrexone bromide. (R)-N-methylnaltrexone bromide, which is also known as "MNTX" and is described in international PCT patent application publication number, WO2006/12789, which is incorporated herein by reference. The chemical name for (R)-N-methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. (R)-N-methylnaltrexone bromide has the molecular formula C₂iH₂₆N0₄Br and a molecular weight of 436.36 g/mol. (R)-N-methylnaltrexone bromide has the following structure:

(R)-N-methylnaltrexone bromide where the compound is in the (R) configuration with respect to the quaternary nitrogen. In certain embodiments presented herein, at least about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the compound is in the (R) configuration with respect to nitrogen. Methods for determining the amount of (R)-N-methylnaltrexone bromide, present in a sample as compared to the amount of (^-N-methylnaltrexone bromide present in that same sample, are described in detail in WO2006/127899, which is incorporated herein by reference. In other embodiments, the methylnaltrexone contains 0.15%, 0.10%, or less (S)-N- methylnaltrexone bromide.

In certain embodiments, A^" is an acidic amphiphilic pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient has a pK_a of about 3 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pK_a of about 2 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pK_a between about 1 and about 2. In certain embodiments, the pharmaceutically acceptable excipient has a pK_a of about 1 or less. In some embodiments, the compositions for oral administration are tablet formulations. In some embodiments, the compositions for oral administration are capsule formulations. Methylnaltrexone for use in such compositions and formulations can be in any of a variety of forms. For example, forms of methylnaltrexone suitable for use in the inventive compositions and formulations include pharmaceutically acceptable salts, prodrugs, polymorphs (i.e., crystal forms), co-crystals, hydrates, solvates, and the like. Any form of methylnaltrexone can be used in the compositions or formulations, but the form should allow for ion pairing with the amphiphilic pharmaceutically acceptable excipient. In certain embodiments, the methylnaltrexone ion pair is a salt that is solid at room temperature. In some embodiments, the composition is a pharmaceutical composition.

In general, formulations for oral administration comprise methylnaltrexone, an amphiphilic pharmaceutically acceptable excipient as described above, and a disintegrant, and further, optionally, comprise one or more other components, such as, for example, binders, carriers, chelating agents, antioxidants, fillers, lubricants, wetting agents, or combinations thereof, as set forth in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein.

In a particular embodiment, the composition, for example, pharmaceutical composition, for oral administration comprises methylnaltrexone bromide and sodium dodecyl (lauryl) sulfate (also known as SDS or SLS). In certain embodiments, the composition further includes sodium bicarbonate as a disintegrant. Additional excipients, as set forth above, can be incorporated, including, but not limited to, at least one of microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate. In one embodiment, the composition for oral administration comprises each of methylnaltrexone bromide, sodium lauryl sulfate, sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate.

Compositions and formulations thereof for use as described herein can be generated as set forth, for example, in U.S. Patent Publication No. 2012/0190702; U.S. Patent No. 8,552,025; U.S. Patent Publication No. 2008/0070975; U.S. Patent No. 8,420,663; and International Publication No. WO2011/112816, each of which is incorporated herein by reference in its entirety. Additionally, compositions, and formulations thereof, can be generated as described in Examples 2-4 herein. The particular mode of administration of the opioid antagonist, generally speaking, can be conducted using any mode of administration that is medically acceptable, e.g., any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, intramuscular, infusion, intravenous, intracavity or subcutaneous. Direct injection could also be used for local delivery. Oral or subcutaneous administration can be suitable for prophylactic or long term treatment because of the convenience of the patient as well as the dosing schedule.

In some embodiments, the opioid antagonists can be administered as an enterically coated tablet or capsule. In some embodiments, the opioid antagonist is administered by a slow infusion method or by a time-release or controlled-release method or as a lyophilized powder.

When administered, the compounds and compositions as disclosed herein are provided in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions or preparations. Such preparations can routinely contain salts, buffering agents, preservatives, and optionally other therapeutic ingredients. When used in medicine, the salts are typically pharmaceutically acceptable salts, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p- toluenesulfonic, tartaric, citric, methanesulfonic, formic, succinic, naphthalene-2-sulfonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic. Suitable buffering agents include, but are not limited to, acetic acid and salts thereof (1-2% WN); citric acid and salts thereof (1-3% WN); boric acid and salts thereof (0.5-2.5% WN); and phosphoric acid and salts thereof (0.8-2% WN).

Suitable preservatives include, but are not limited to, benzalkonium chloride (0.003- 0.03% WN); chlorobutanol (0.3-0.9% WIN); parabens (0,01-0.25% WN) and thimerosal (0.004-0.02% WN).

For ease of administration, a pharmaceutical composition of the peripheral opioid antagonist can also contain one or more pharmaceutically acceptable excipients, such as lubricants, diluents, binders, carriers, and disintegrants. Other auxiliary agents can include, e.g., stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, coloring, flavoring and/or aromatic active compounds.

A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. For example, suitable pharmaceutically acceptable carriers, diluents, solvents or vehicles include, ,but are not limited to, water, salt (buffer) solutions, alcohols, gum arabic, mineral and vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, vegetable oils, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like.

If a pharmaceutically acceptable solid carrier is used, the dosage form of the analogs can be in the form of, for example, tablets, capsules, powders, suppositories, or lozenges. If a liquid carrier is used, exemplary forms such as soft gelatin capsules, syrups or liquid suspensions, emulsions or solutions can be the dosage form.

For parental application, particularly suitable are injectable, sterile solutions, preferably nonaqueous or aqueous solutions, as well as dispersions, suspensions, emulsions, or implants, including suppositories. Ampoules are often convenient unit dosages. Injectable depot forms can also be suitable and can be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.

Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.

For enteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules such as soft gelatin capsules. A syrup, elixir, or the like can be used wherein a sweetened vehicle is employed. Other delivery systems can include, for example, time-release, delayed-release or sustained-release delivery systems. Such systems can avoid repeated administrations of the compounds of the invention, increasing convenience to the patient and the physician and maintain sustained plasma levels of compounds. Many types of controlled-release delivery system are available and known to those of ordinary skill in the art. Sustained- or controlled- release compositions can be formulated, e.g., as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, and the like.

For example, the compounds and compositions as disclosed herein can be combined with pharmaceutically acceptable sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. An exemplary sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix can be desirably chosen from biocompatible materials such as liposomes, polymer-based system such as polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly (ortho )esters, polysaccharides, polyamino acids, hyaluronic acid, collagen, chondroitin sulfate, polynucleotides, polyvinyl propylene, polyvinyl pyrrolidone, and silicone; nonpolymer system such as carboxylic acids, fatty acids, phospholipids, amino acids, lipids such as sterols, hydrogel release system; silastic system; peptide-based system; implants and the like. Specific examples include, but are not limited to: (a) erosional system in which the polysaccharide is contained in a form within a matrix, described, for example, in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152 (each of which is incorporated herein by reference in its entirety), and (b) diffusional system in which an active component permeates at a controlled rate from a polymer, such as that described in U.S. Pat. Nos. 3,854,480,5,133,974 and 5,407,686 (each of which is incorporated herein by reference in its entirety). In addition, pump-based hard-wired delivery system can be used, some of which are adapted for implantation. Suitable enteric coatings are described in, for example, International Publication No. WO 1998/025613 and U.S. Pat. No. 6,274,591, each of which is incorporated herein by reference in its entirety.

Use of a long-term sustained-release implant can be suitable for treatment of chronic conditions. The implant can be constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and optionally for from about 30 to 60 days. Long-term sustained-release implants are well-known to those of ordinary skill in the art and include some of the release system described above.

With respect to methylnaltrexone, aqueous formulations can include chelating agent, a buffering agent, an anti-oxidant and, optionally, an isotonicity agent, preferably pH adjusted to between 3.0 and 3.5. Preferred such formulations that are stable to autoclaving and long term storage are described, for example, in U.S. Patent No. 8,552,025, the disclosure of which is incorporated herein by reference in its entirety.

In some embodiments, compounds of the invention are administered in a dosing regimen which provides a continuous dosing regimen of the compound to a subject, e.g., a regimen that maintains minimum plasma levels of the opioid antagonist, and preferably eliminates the spikes and troughs of a drug level with conventional regimens. Suitably, a continuous dose can be achieved by administering the compound to a subject on a daily basis using any of the delivery methods disclosed herein. In some embodiments, the continuous dose can be achieved using continuous infusion to the subject, or via a mechanism that facilitates the release of the compound over time, for example, a sustained release formulation. Suitably, compounds of the invention are continuously released to the subject in amounts sufficient to maintain a concentration of the compound in the plasma of the subject effective to reduce or inhibit opioid-induced side effects. The compounds and compositions as disclosed herein, whether provided alone or in combination with other therapeutic agents, are provided in a therapeutically effective amount. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.

If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. Those of ordinary skill in the art can readily determine effective doses and co-administration regimens (as described herein) as determined by good medical practice and the clinical condition of the individual patient.

In some embodiments of the invention, the opioid antagonists are co-administered with the opioid. The term "co-administration" is meant to refer to a combination therapy by any administration route in which two or more agents are administered to a patient or subject. Co-administration of agents can also be referred to as combination therapy or combination treatment. The agents can be in the same dosage formulations or separate formulations. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be administered concurrently, or they each can be administered at separately staggered times. The agents can be administered simultaneously or sequentially (e.g., one agent can directly follow administration of the other or the agents can be give episodically, e.g., one can be given at one time followed by the other at a later time, e.g., within a week), as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body. The agents can also be administered by different routes, e.g., one agent can be administered intravenously while a second agent is administered intramuscularly, intravenously or orally. In other words, the coadministration of the opioid antagonist compound in accordance with the present invention with an opioid is suitably considered a combined pharmaceutical preparation which contains an opioid antagonist and a opioid agent, the preparation being adapted for the administration of the peripheral opioid antagonist on a daily or intermittent basis, and the administration of opioid agent on a daily or intermittent basis. Thus, the opioid antagonists can be administered prior to, concomitant with, or after administration of the opioids. Co- administrable agents also can be formulated as an admixture, as, for example, in a single formulation or single tablet. These formulations can be parenteral or oral, such as the formulations described, e.g., in U.S. Pat. Nos. 6,277,384; 6,261,599; 5,958,452 and International Publication No. WO 98/25613, each of which is incorporated herein by reference in its entirety.

The compounds and compositions disclosed herein are useful in antagonizing undesirable side effects of opioid analgesic therapy (e.g., gastrointestinal effects (e.g., delayed gastric emptying, altered GI tract motility), etc.). Furthermore, a provided compound or composition can be used as to treat subjects having disease states that are ameliorated by binding μ opioid receptors, or in any treatment wherein temporary suppression of the μ opioid receptor system is desired (e.g., ileus, etc.). Accordingly, administration of the compounds and compositions disclosed herein can be advantageous for treatment, prevention, amelioration, delay or reduction of side effects of opioid use, such as, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with use of narcotic analgesia, etc, or combinations thereof. Use of a provided compound or composition as disclosed herein can thus be beneficial from a quality of life standpoint for subjects receiving opioids, as well as to reduce complications arising from chronic constipation, such as hemorrhoids, appetite suppression, mucosal breakdown, sepsis, colon cancer risk, and myocardial infarction.

In some embodiments, a provided compound or composition as disclosed herein is useful for administration to a subject receiving acute opioid administration. In some embodiments, a provided compound or composition is useful for administration to subjects suffering from postoperative gastrointestinal dysfunction.

In some embodiments, a provided compound or composition as disclosed herein is useful for administration to subjects receiving chronic opioid administration (e.g., terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; subjects receiving opioid therapy for maintenance of opioid withdrawal). In some embodiments, the subject is a subject using opioid for chronic pain management. In some embodiments, the subject is a terminally ill patient. In other embodiments the subject is a person receiving opioid withdrawal maintenance therapy. Chronic opioid administration can refer to, or can be characterized by, the need for substantially higher levels of opioid to produce the therapeutic benefit as a result of prior opioid use. Chronic opioid administration can include, for example, daily opioid treatment for a week or more, or intermittent opioid use for at least two weeks.

In some embodiments, a provided compound or composition as disclosed herein can be useful in treating, reducing, inhibiting, or preventing the effects of opioid use including, e.g., aberrant migration or proliferation of endothelial cells (e.g., vascular endothelial cells), increased angiogenesis, and increase in lethal factor production from opportunistic infectious agents (e.g., Pseudomonas aeruginosa). Additional advantageous uses of a provided compound or composition include treatment of opioid-induced immune suppression, inhibition of angiogenesis, inhibition of vascular proliferation, treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases and diseases of the musculokeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, and treatment of autoimmune diseases.

In some embodiments, a provided compound or composition as disclosed herein can be used in methods for preventing, inhibiting, reducing, delaying, diminishing or treating gastrointestinal dysfunction, including, but not limited to, irritable bowel syndrome, opioid- induced bowel dysfunction, colitis, post-operative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of the stomach, and small and/or large intestinal propulsion, increased amplitude of non-propulsive segmental contractions, constriction of sphincter of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distention, diminished gastric, biliary, pancreatic or intestinal secretions, increased absorption of water from bowel contents, gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominal or epigastric pam and discomfort, constipation, idiopathic constipation, post-operative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy takedown, low anterior resection», and delayed absorption of orally administered medications or nutritive substances.

Provided forms of a provided compound or composition as disclosed herein are also useful in treatment of conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of inflammation associated disorders (e.g., irritable bowel syndrome), immune suppression, chronic inflammation.

In still further embodiments, veterinary applications (e.g., treatment of domestic animals, e.g. horse, dogs, cats, etc.) of use of a provided compound or composition are provided. Thus, use of provided formulations in veterinary applications analogous to those discussed above for human subjects is contemplated. For example, inhibition of equine gastrointestinal motility, such as colic and constipation, can be fatal to a horse. Resulting pain suffered by the horse with colic can result in a death-inducing shock, while a long-term case of constipation can also cause a horse's death. Treatment of equines with peripheral opioid receptor antagonists has been described, e.g., in U.S. Patent Publication No. 20050124657 published January 20, 2005. In other embodiments, a provided compound or composition and unit dose forms are useful in preparation of medicaments, including, but not limited to medicaments useful in the treatment of side effects of opioid use (e.g., gastrointestinal side effects (e.g., inhibition of intestinal motility, 01 sphincter constriction, constipation) nausea, emesis, vomiting, dysphoria, pruritus, etc.) or a combination thereof. Compounds of the present invention, and pharmaceutically acceptable compositions and formulations thereof, are useful for preparations of medicaments, useful in treatment of patients receiving acute opioid therapy (e.g., patients suffering from post-operative gastrointestinal dysfunction receiving acute opioid administration) or subjects using opioids chronically (e.g., terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; or subjects receiving opioid therapy for maintenance of opioid withdrawal). Still further, preparation of medicaments useful in the treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases, treatment of diseases of the musculokeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune suppression, therapy of post-operative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy take down, low anterior resection), idiopathic constipation, and ileus (e.g., post-operative ileus, post-partum ileus), and treatment of disorders such as cancers involving angiogenesiss, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.

Embodiments disclosed herein may be of therapeutic value in opioid antagonist treatment for patients who have tumors. Such tumors include, but are not limited to adrenal cortical carcinoma, tumors of the bladder: squamous cell carcinoma, urothelial carcinomas; tumors of the bone: adamantinoma, aneurysmal bone cysts, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, fibrous dysplasia of the bone, giant cell tumour, osteochondroma, osteosarcoma; breast tumors: secretory ductal carcinoma, chordoma; colon tumors: colorectal adenocarcinoma; eye tumors: posterior uveal melanoma, fibrogenesis imperfecta ossium, head and neck squamous ceil carcinoma; kidney tumors: chromophobe renal cell carcinoma, clear cell renal cell carcinoma, nephroblastoma (Wilms tumor), kidney: papillary renal cell carcinoma, primary renal ASPSCR.1-TFE3 tumor, renal cell carcinoma; liver tumors: hepatoblastoma, hepatocellular carcinoma; lung tumors: non- small cell carcinoma, small cell cancer; malignant melanoma of soft parts; nervous system tumors: medulloblastoma, meningioma, neuroblastoma, astrocytic tumors, ependymomas, peripheral nerve sheath tumors, phaeochromocytoma; ovarian tumors: epithelial tumors, germ cell tumors, sex cord-stromal tumors, pericytoma; pituitary adenomas; rhabdoid tumor; skin tumors: cutaneous benign fibrous histiocytomas; smooth muscle tumors: intravenous leiomyomatosis; soft tissue tumors: liposarcoma, myxoid liposarcoma, low grade fibromyxoid sarcoma, leiomyosarcoma, alveolar soft part sarcoma, angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma, desmoplastic small round cell tumor, elastofibroma, Ewing's tumors, extraskeletal myxoid chondrosarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma/benign lipomatous tumors, liposarcoma/malignant lipomatous tumors, malignant myoepithelioma, rhabdomyosarcoma, synovial sarcoma, squamous ceil cancer; tumors of the testis: germ cell tumors, spermatocyte seminoma; thyroid tumors: anaplastic (undifferentiated) carcinoma, oncocytic tumors, papillary carcinoma; uterus tumors: carcinoma of the cervix, endometrial carcinoma, leiomyoma etc. Embodiments are also directed to the provision of a method of treating abnormal tumors, comprising administering to a patient in need of such treatment, an effective amount of an opioid antagonist.

In certain aspects, the selection of certain subjects suffering from opioid induced constipation for treatment with oral compositions of methylnaltrexone and subsequent administration of the oral compositions is presented herein.

As defined herein, a subject suffering from opioid induced constipation refers to a subject who suffers from constipation resulting from opioid activity, for example, exogenous opioid therapy or endogenous opioid activity. "Constipation" refers to a condition in which a subject suffers from infrequent bowel movements or bowel movements that are painful and/or hard to pass. A subject experiencing constipation often suffers from hard or lumpy stools, straining during bowel movements and/or a sensation of incomplete evacuation following bowel movements. In a particular embodiment, constipation refers to a subject who experiences less than three (3) rescue free bowel movements (RFBMs) per week on average, for example, over the course of the last four consecutive weeks, wherein "rescue free bowel movement" refers to the passage and evacuation of feces, or laxation.

Subjects taking opioids routinely stop taking their opioid medications due to constipation, thus there is a need in the art for a method to reduce OIC. The methods described herein improve a subject's compliance with opioid treatment. Increasing or improving compliance with opioid treatment, as used herein, includes, for example, a subject continuing on opioid treatment due to increased bowel movements due to methylnaltrexone administration. Subjects experience less pain due to compliance with opioid treatment and thus do not experience withdrawal symptoms. Opioid withdrawal symptoms include, for example, dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. Decreasing opioid withdrawal leads to fewer hospitalizations.

In certain embodiments, the subject does not have a history of chronic constipation prior to the initiation of opioid therapy.

Subjects who are on opioid therapy, who have recently been on opioid therapy or who intend to be on opioid therapy, can be administered the oral compositions of methylnaltrexone. In one embodiment, the subject, at the time of the screening, is on an opioid therapeutic regimen and has been on such regimen for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days. In a particular embodiment, the subject has been taking opioids for at least one month. In another embodiment, the subject, at the time of the screening, will begin an opioid therapeutic regimen at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days after the screening. In yet another embodiment, the subject, at the time of the screening, will have discontinued opioid therapeutic regimen less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days prior to the screening.

The subject can be on an opioid regimen for a variety of purposes. For example, the subject can be a cancer or surgical patient, an immunosuppressed or immunocompromised patient (including HIV infected patient), a patient with advanced medical illness, a terminally ill patient, a patient with neuropathies, a patient with rheumatoid arthritis, a patient with osteoarthritis, a patient with chronic back pain, a patient with spinal cord injury, a patient with chronic abdominal pain, a patient with chronic pancreatic pain, a patient with pelvic perineal pain, a patient with fibromyalgia, a patient with chronic fatigue syndrome, a patient with migraine or tension headaches, a patient on hemodialysis, or a patient with sickle cell anemia. In various embodiments, the subject is receiving opioids for alleviation of pain. In a particular embodiment, the subject is receiving opioids for alleviation of chronic non- malignant pain. As used herein, the term "non-malignant pain" refers to pain originating from a non-malignant source such as cancer. In particular embodiments, non-malignant pain includes to back pain, cervical pain, neck pain, fibromyalgia, low extremity pain, hip pain, migraines, headaches, neuropathic pain, or osteoarthritis.

As used herein, the term "chronic" refers to a condition that persists for an extended period of time. In various embodiments, chronic can refer to a condition that lasts at least 1, 2, 3 or 4 weeks. Alternatively, chronic can refer to a condition that lasts at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 or 36 months. In a particular embodiment, the subject is receiving opioids for alleviation of chronic non-malignant pain that has persisted for at least 2 months.

In various embodiments, the subject can be on opioid therapy including, but not limited to, alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and/ or tramadol.

Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal administration. By "morphine equivalent dosage" is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 μg fentanyl.

In some embodiments, the subject is receiving a daily dose of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg of oral morphine equivalents. In a particular embodiment, the subject is receiving at least 50 mg of oral morphine equivalents. Calculation of oral morphine equivalents is well known in the art. Table A provides a morphine oral equivalence table for known opioids. Table A: Morphine Oral Equivalence Table

OXYMORPHONE HYDROCHLORIDE PO mg 3

DARVOCET PO mg 0.234

DARVOCET-N PO mg 0.15

DARVON PO mg 0.234

DARVON-N PO mg 0.15

PROPOXYPHENE PO mg 0.234

REMIFENTANIL IV meg 0.6

ROXICET PO mg 2

SUFENTANIL IV mg 6000

SUFENTANIL IV meg 6

TRAMADOL PO mg 0.2

TRAMADOL HYDROCHLORIDE PO mg 0.2

TRAMAL PO mg 0.2

ULTRACET PO mg 0.2

TAPENTADOL PO mg 0.33

Foley KM. The treatment of cancer pain. N Engl J Med. 1985 Jul, 3 3(2):84-95

The subject's opioid therapeutic regimen can be by any mode of administration. For example, the subject can be taking opioids orally, transdermally, intravenously, or subcutaneously.

Generally, oral doses of the opioid antagonists, particularly peripheral antagonists, will range from about 0.01 to about 80 mg/kg body weight per day. In some embodiments, the oral dose of opioid antagonists range from about 1 to 20 mg/kg body weight.

In some embodiments, the amount of opioid antagonist that is orally administered ranges from about 1 mg to about 1 g. In some embodiments, the amount of opioid antagonist that is orally administered ranges from about 10 mg to about 600 mg. In some embodiments, the amount of opioid antagonist that is orally administered ranges from about 75 mg to about 900 mg. In some embodiments, the amount of opioid antagonist that is orally administered is about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg, or any amount included therein. The opioid antagonist can be administered once a day, twice a day, three times a day, four times a day or five times day, or as needed.

Generally, parenteral administration, including intravenous and subcutaneous administration, will range from about 0.001 to about 5 mg/kg body weight. In some embodiments, doses administered intravenously or subcutaneously range from about 0.05 to about 0.5 mg/kg body weight. In some embodiments, doses administered intravenously or subcutaneously range from about 0.075 to about 0.6 mg/kg body weight. In some embodiments, doses administered intravenously or subcutaneously range from about 0.05 to about 0.3 mg/kg body weight.

In some embodiments, doses administered intravenously are about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg or about 0.5 mg/kg body weight, or any amount that is included therein. The doses administered intravenously can be administered on a continuous basis. In some embodiments, the intravenous doses can be administered every 6 hours, every 12 hours, or every 24 hours for a period of from about 5 to 15 days, or from about 7 to 10 days. In some embodiments, the intravenous doses are administered for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days or about 15 days.

In some embodiments, doses administered subcutaneously are about 0.005 mg/kg, about 0.01 mg/kg, about 0.015 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg or about 0.45 mg/kg body weight, or any amount that is included therein. The subcutaneous dose can be administered every day or every other day. In some embodiments, the subcutaneous dose is not administered more than once in a 24-hour period. In some embodiments, the subcutaneous dose is administered on an as needed basis. In some embodiments, the subcutaneous dose is administered at least once per week.

Dosages can be adjusted appropriately to achieve desired drug levels, local or systemic, depending on the mode of administration. For example, the dosage for oral administration of the opioid antagonists in an enteric ally coated formulation can be from about 10 to 30% of the non-coated oral dose. In the event that the response in a patient is insufficient of such doses, even higher doses (or effectively higher dosages by a different, more localized delivery route) can be employed to the extent that the patient tolerance permits. Multiple doses per day can be administered to achieve appropriate systemic levels of compounds. Appropriate system levels can be determined by, for example, measurement of the patient's plasma level of the drug using routine HPLC methods known to these of skill in the art.

In some embodiments, methylnaltrexone is administered at a dosage of: 0.001 to 1.0 mg/kg body weight for intravenous administration; 0.001 to 1.0 mg/kg body weight for intramuscular administration; 0.001 to 1.0 mg/kg body weight for transmucosal administration and 0.1 to 40.0 mg/kg body weight for oral administration.

The administration of the methylnaltrexone can be commenced prior to administration of the opioid to prevent opioid-induced side effects, including constipation. In some embodiments, administration of methylnaltrexone commences about 5 minutes for parenteral MNTX administration and 20 minutes for enteral MNTX administration prior to administration of opioids in order to prevent these opioid-induced side effects. While the prevention of symptoms is preferred, in some patients, such as those chronically on opioids, prevention is not possible. However, methylnaltrexone administration can also be commenced after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.

Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone.

In the description above and below, methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNMs can be used as desired, and appropriate dosage can readily be determined empirically by those of skill in the art to account for e.g., variable affinity of the QDNM for opiate receptors, different formulations, etc.

Compositions and formulations can be administered to a patient as required to provide an effective amount of methylnaltrexone. As defined above, an "effective amount" of a compound or pharmaceutically acceptable composition can achieve a desired therapeutic and/or prophylactic effect. In some embodiments, an "effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating or preventing one or more symptoms of opioid induced constipation, as defined herein. In some embodiments, the term "effective amount," as used in connection with an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof, refers to an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof sufficient to achieve a rescue free or spontaneous bowel movement in a subject.

In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement in a subject within about 24 hours, within about 12 hours, within about 8 hours, within about 5 hours, within about 4 hours, within about 3 hours, within about 2 hours, or within about 1 hours of administration to said patient. In a particular embodiment, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient. In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient for at least 100%, 99%, at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, or at least 50% of all doses administered. In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement within four hours during the first 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of dosing. In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient for all doses administered during first four weeks of dosing.

The efficacy of the compositions presented herein in treating opioid induced constipation can further be assessed by an increase in the number of rescue free bowel movements experienced by a subject. For example, in some embodiments, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In particular embodiments, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1. In another embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 2. In yet another embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 3. In certain embodiments, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject during the first 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of dosing. In a particular embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1 during the first 4 weeks of dosing. In another particular embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements by at least one to at least 3 a week. In yet a further embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements by at least one to at least 3 a week for at least 3 of the first 4 weeks following administration.

The efficacy of the compositions presented herein can be further assessed using various assessment tools available to those skilled in the art to assess treatment of constipation.

In some embodiments, the efficacy of the compositions of methylnaltrexone is assessed by Patient Assessment of Constipation (PAC) questionnaires. The PAC consists of two complementary questionnaires: the PAC-Symptoms (SYM) and the PAC-Quality of Life (QoL) questionnaires. The PAC-SYM is a 12 item survey that measures the severity of constipation symptoms across three domains: stool symptoms, rectal symptoms and abdominal symptoms. The PAC-SYM scale has been used primarily to evaluate chronic constipation. The PAC-SYM scale is further described in Frank et al. Scand J Gastroenterol (1999) 34(9):870-877 and Slappendel et al. European Journal of Pain (2006) 10(3):209-217, the entire contents of each of which are incorporated by reference herein. The PAC-QoL is a 28-item survey that measures constipation-specific quality of life across four domains: worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction. The PAC-QoL scale is further described in Marquis et al. SJG (2005) 40:540-551, the entire contents of which are incorporated by reference herein.

Alternatively or in combination, the efficacy of the compositions as described herein can be assessed by the European Quality of Life-5 Dimensions (EQ-5D) analysis. The EQ-5D is a 5-item standardized instrument for use as a measure of patient reported outcome (PRO). Applicable to a wide range of health conditions and treatments, the instrument provides a simple descriptive profile and a single index value for health status. The EQ-5D instrument is further described in Dolan P. Medical Care (1997) 35:1095-1108, Rabin R. Ann. Med. (2001) 33(5):537-543 and Shaw et al. Medical Care (2005) 43:203-220, the entire contents of each of which are incorporated by reference herein.

Alternatively or in combination, the efficacy of the compositions as described herein is assessed by the Work Productivity and Activity Impairment General Health V2.0 (WPALGH) questionnaire. The WPALGH is a 6-item questionnaire to quantify lost time from work and loss in productivity for health problems. The WPALGH yields 4 types of scores: absenteeism (work time missed), "presenteeism" (impairment at work/reduced on-the- job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment. The WPALGH questionnaire is further described in Reilly et al. PharmacoEconomics (1993) 4(5):353-365, the entire contents of which are incorporated by reference herein.

Alternatively or in combination, the efficacy of the compositions as described herein can be assessed by the Global Clinical Impression of Change (GCIC) scale. The GCIC is a 7 point rating scale designed to assess subject's and clinician's impression of the subject's change in bowel status while on study drug. The scale ranges from 1 (Much Worse) to 7 (Much Better). This scale was completed by the subject and clinician at the end of daily dosing and End of Treatment.

In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone about once a day. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone about once every other day. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone on an as-needed basis. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone on an as-needed basis and at least once per week.

In some embodiments, the subject is subcutaneously administered from about 6 mg to about 15 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered from about 8 mg to about 12 mg of methylnaltrexone, or a salt thereof, daily or every other day. For example, the subject can be administered about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, or any other amount included therein, of methylnaltrexone, or salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered about 8 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered about 12 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered 8 mg or 12 mg of methylnaltrexone, or a salt thereof, every other day, as needed, but not more frequently than once in a 24-hour period.

In some embodiments, the subject is subcutaneously administered methylnaltrexone or a salt thereof, at a dose of between about 0.05 mg/kg to about 0.45 mg/kg body weight daily or every other day. In some embodiments, the subject is subcutaneously administered methylnaltrexone or a salt thereof, at a dose of between about 0.10 mg/kg to about 0.30 mg/kg body weight daily or every other day. For example, the subject can be administered methylnaltrexone, or a salt thereof, at a dose of about 0.05 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.35 mg/kg, about 0.40 mg/kg, about 0.45 mg/kg body weight, or any amount included therein, daily or every other day. In some embodiments, the subject is administered methylnaltrexone, or a salt thereof, at a dose of about 0.15 mg/kg body weight daily or every other day.

In some embodiments, the subject is subcutaneously administered methylnaltrexone, or a salt thereof, methylnaltrexone or a salt thereof, at a dose of between about 0.05 mg/kg to about 0.45 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period. In some embodiments, the subject is subcutaneously administered methylnaltrexone, or a salt thereof, methylnaltrexone or a salt thereof, at a dose of between about 0.10 mg/kg to about 0.30 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period. In some embodiments, the subject is subcutaneously administered methylnaltrexone, or a salt thereof, at a dose of 0.15 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period.

In some embodiments, the patient or subject is orally administered a composition of methylnaltrexone at least once a day. In some embodiments, the patient or subject is administered an oral composition of methylnaltrexone at least once, twice, three, four or five times a day. In some embodiments, the patient or subject is administered an oral composition of methylnaltrexone three times a day.

In some embodiments, the subject is orally administered from about 150 mg to about 450 mg of methylnaltrexone, or a salt thereof, per day. In some embodiments, the subject is orally administered from about 150 mg to about 300 mg of methylnaltrexone, or a salt thereof, per day. In some embodiments, the subject is administered an oral dose of methylnaltrexone in the form of a tablet or capsule. In various embodiments, the subject is orally administered 150 mg of methylnaltrexone, or a salt thereof, daily. For example, the subject can be administered a tablet comprising 150 mg of methylnaltrexone or a salt thereof, daily. In another embodiment, the subject is orally administered 300 mg of methylnaltrexone or a salt thereof, daily. For example, the subject can be administered two tablets, each comprising 150 mg of methylnaltrexone or a salt thereof, daily. In yet another embodiment, the subject is orally administered 450 mg of methylnaltrexone or a salt thereof, daily. For example, the subject can be administered three tablets, each comprising 150 mg of methylnaltrexone or a salt thereof, daily.

Presented herein are methods that can be predicated, at least in part, on the identification that administration of compositions as described herein is sufficient to treat opioid induced constipation without effecting adverse events. Exemplary adverse events induced by the administering oral methylnaltrexone include, but are not limited to, atrial flutter, faecaloma, impaired gastric emptying, chest pain, drug withdrawal syndrome, non- cardiac chest pain, hypersensitivity, bronchitis, cellulitis, infectious enterocolitis, gastroenteritis, influenza, osteomyelitis, pneumonia, urinary tract infection, dehydration, inadequate control of diabetes mellitus, diabetic ketoacidosis, hyperkalaemia, lumbar spinal stenosis, depression, suicidal tendencies, dyspnoea, pleurisy, pulmonary embolism, skin ulcer, knee arthoplasty, and spinal fusion surgery.

Also provided herein is a method of decreasing the risk of a cardiovascular event a subject suffering from opioid-induced constipation, comprising administering a composition comprising methylnaltrexone to the subject. In some embodiments, the methylnaltrexone is administered subcutaneously. In some embodiments, the methylnaltrexone is administered orally. In some embodiments, the subject is receiving opioids chronically. In some embodiments, administration of the composition results in a decrease of about one point in a bowel movement straining scale. In some embodiments, administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale). In some embodiments, the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks. The cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.

Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone described herein that decrease the occurrence of adverse events in comparison to the frequency of adverse events observed with previous oral methylnaltrexone formulations, for example, enterically coated oral formulations of methylnaltrexone or other oral formulations of methylnaltrexone not including an anion of an amphiphilic pharmaceutically acceptable excipient, in particular, sodium dodecyl (lauryl) sulfate.

For example, the data presented in Example 1 demonstrate that the methods of administering the oral formulations of methylnaltrexone described herein are safer than the methods of administering previously described oral formulations of methylnaltrexone, for example, enterically coated oral formulations of methylnaltrexone or other oral formulations of methylnaltrexone that do not include an anion of an amphiphilic pharmaceutically acceptable excipient, in particular, sodium dodecyl (lauryl) sulfate.

Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from renal impairment. In some embodiments, the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from renal impairment. For example, the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.

Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from hepatic impairment. In some embodiments, the subject suffers from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C). In some embodiments, the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from hepatic impairment. For example, the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day. Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein administration of the oral formulation does not cause any drug- drug interactions. In some embodiments, administration of the oral formulation is considered to have a cleaner safety profile than that of another formulation comprising an opioid antagonist. In some embodiments, administration of the oral formulation can be administered concurrently with a composition that includes a CYP450 isozyme substrate.

Embodiments also relate to methods of predicting a clinical response to administration of methylnaltrexone, wherein the methods include administering an a composition comprising methylnaltrexone to a subject and analyzing the subject's plasma MNTX concentration, wherein a measurement of C_max > 100 ng/mL indicates that the subject is a responder. In some embodiments, the clinical response is a laxation response within about four hours of administration of methylnaltrexone. In some embodiments, prediction of the clinical response indicates a likely response regardless of the route of administration of methylnaltrexone. For example, in some embodiments, a clinical response based on measurement of C_max after subcutaneous administration of methylnaltrexone is an indication that clinical response will occur in the subject after administration of methylnaltrexone by a non-subcutaneous route.

All features of each of the aspects presented herein apply to all other aspects mutatis mutandis. The contents of all references, patents, pending patent applications and published patents, cited throughout this application are hereby expressly incorporated by reference.

EXAMPLES

EXAMPLE 1: EFFICACY AND DOSAGE STUDIES OF ORAL

METHYLNALTREXONE IN TREATMENT OF OPIOID INDUCED CONSTIPATION

A study was conducted to evaluate the safety and efficacy of Oral Methylnaltrexone (OM, Example 3) versus placebo in subjects with chronic non-malignant pain who have Opioid Induced Constipation (OIC). In a, multicenter, randomized, double-blind, placebo- controlled, parallel-group study of OM for the treatment of OIC, approximately 802 subjects with chronic non-malignant pain were evaluated.

Constipation was defined as < 3 Rescue-Free Bowel Movements (RFBMs) per week on average (no laxative use within 24 hours prior to bowel movement) that were associated with 1 or more of the following (based on subject's diary report):

a. A Bristol Stool Form Scale type 1 or 2 for at least 25% of the rescue-free bowel movements. b. Straining during at least 25% of the rescue-free bowel movements. c. A sensation of incomplete evacuation after at least 25% of the rescue-free bowel movements.

Subjects who remained eligible at the baseline visit (day 1) were randomly assigned to either OM tablet formulation 150 mg, 300 mg, 450 mg, or placebo initially in a 1: 1: 1: 1 allocation ratio. Subjects were required to take three tablets per day, first thing in the morning on an empty stomach (prior to breakfast). Subjects were instructed to swallow the tablets whole and never to chew, divide, or crush them and wait at least one half hour before ingesting any food. Subjects participated in the study for up to 84 days. The first 28 days were once daily dosing; the remaining 56 days were dosing as needed (PRN). Dosing remained double -blind throughout the 12 week period (84 days). The 84 day treatment period were followed by a 14-day post-treatment follow-up period (+ 2 days). Enrollment continued until a total of approximately 802 subjects had been randomized and dosed.

The efficacy endpoint of this study was the average proportion of rescue-free laxation responses per subject within 4 hours of all doses during the first four weeks of dosing. The other efficacy endpoints include: Change in weekly number of RFBM from baseline during Weeks 1 to 4; and

Response (responder/non-responder) to study drug during Weeks 1 to 4, where responder was defined as having > 3 RFBM/week, with at least 1 RFBM/week increase over baseline, for at least 3 out of the first 4 weeks

To assess for efficacy, subject-reported information including date and time of bowel movements, Bristol Stool Form Scales, Straining Scales, Sense of Complete Evacuation Scales, and recording of study drug and rescue laxative use.used.

Subjects were monitored for adverse events (AEs), serious adverse events (SAEs) concomitant treatments including opioid use and rescue laxatives, and vital sign measurements at all office visits. Vital signs, physical examinations (including rectal examination), laboratory evaluations, serum/urine pregnancy tests, ECGs, the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS) and the Pain Intensity scale were performed at scheduled intervals during the study.

Standard 12-lead ECGs were obtained after the subject had been resting for at least five minutes at the visits designated in the Schedule of Study Visits and Evaluations. The Investigator was responsible for reviewing, interpreting, and retaining hard copies of the reports. Clinically significant abnormalities at any time point after the normal or non- clinically significant screening ECG were recorded as adverse events, as defined below.

Self-administered PRO endpoints were measured by the PAC-SYM, the PAC-QoL, the EQ-5D, the WPALGH, and GCIC (administered by the clinician) assessments quantify the subjects' constipation symptoms, constipation-related quality of life, overall quality of life, change in bowel status, and degree of interference with ability to work.

Measures of pain were recorded using The Numerical Rating of Pain Intensity Scale. The scale, an 11-point rating scale ranging from 0 (None) to 10 (Worst Pain Possible), is a subject assessment tool and subjects should complete the evaluation based on their pain experienced during the 24 hours prior to completing the scale.

Measures of stool consistency and straining were recorded for each bowel movement using the Bristol Stool Scale. The Bristol Stool Scale is a 7-point scale rating the characteristics of the stool sample. The range is from Type 1, Separate hard lumps, like nuts (hard to pass) to Type 7, Watery, no solid pieces, entirely liquid. The Bristol Stool Scale is a recognized, general measure of stool consistency or form.

Measures of straining were recorded for each bowel movement using the Straining Scale. The scale, a five-point scale to rate the amount of straining (None to Very Severe), is a subject assessment tool and subjects were to complete the evaluations for each bowel movement.

Measures of the sense of complete evacuation were recorded for each bowel movement using the Sense of Complete Evacuation Scale. The scale is a subject assessment tool and subjects were to complete the evaluations for each bowel movement.

The PROs are for the purpose of exploring the subject's experience of constipation symptoms and the impact of constipation on quality of life and work productivity. Every effort was to be made to maintain an unbiased assessment. The investigator was to not influence the subject's self-assessments.

Patient Assessment of Constipation (PAC): The PAC consists of two complementary questionnaires: the PAC-Symptoms (SYM) and the PAC-Quality of Life (QoL). The PAC-SYM is a 12 item survey that measures the severity of constipation symptoms across three domains: stool symptoms, rectal symptoms and abdominal symptoms. The PAC-SYM scale has been use primarily to evaluate chronic constipation. The PAC-QoL is a 28-item survey that measures constipation- specific quality of life across four domains: worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction.

European Quality of Life-5 Dimensions (EQ-5D): The EQ-5D is a 5-item standardized instrument for use as a measure of PRO. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status.

Work Productivity and Activity Impairment General Health V2.0 (WPAIrGH):

The WPALGH is a 6-item questionnaire to quantify lost time from work and loss in productivity for health problems. The WPALGH yields 4 types of scores: absenteeism (work time missed), "presenteeism" (impairment at work/reduced on-the-job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment.

Global Clinical Impression of Change (GCIC): The GCIC is a 7 point rating scale designed to assess subject's and clinician's impression of the subject's change in bowel status while on study drug. The scale ranges from 1 (Much Worse) to 7 (Much Better). This scale was completed by the subject and clinician at the end of daily dosing (Visit 4) and End of Treatment (Visit 7).

803 subjects enrolled in the study. Of the 201 subject receiving placebo, 186 subjects completed the study. Of the 201 subjects receiving 150 mg oral methylnaltrexone daily, 187 subjects completed the study. Of the 201 subjects receiving 300 mg oral methylnaltrexone daily, 189 subjects completed the study. Finally, of the 200 subjects receiving 450 mg oral methylnaltrexone daily, 179 subjects completed the study.

The nature non-malignant chronic pain experienced by all subjects included, for example, back pain, joint/extremity pain, arthritis, neurologic/ neuropathic pain or fibromyalgia. Results demonstrated efficacy of the oral compositions of methylnaltrexone for each of the tested dosages, i.e., 150 mg, 300 mg and 450 mg of methylnaltrexone. Such efficacy is evidenced by demonstration of an efficacy endpoint, e.g.., the average proportion of rescue free bowel movements per subject within 4 hours of all doses during the first 4 weeks of dosing. Additional details can be found in U.S. Patent Publication No. 2013- 0317050, which is incorporated herein by reference in its entirety.

Results further demonstrate that study drug, at dosages of 150 mg, 300 mg and 450 mg, did not result in adverse events as set forth in each of Figure 1 (all adverse events), Figure 2 (serious adverse events organized by organ system class) and Figure 3 (adverse events organized by organ system class).

Finally, Figure 4 summarizes clinically significant electrocardiogram results from the study.

EXAMPLE 2: PREPARATION OF TABLETS OF METHYLNALTREXONE

BROMIDE

Methylnaltrexone bromide can be prepared, for example, according to the methods described in detail in international PCT Patent Application publication number, WO 2006/127899. Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients. Spheroids containing methylnaltrexone were prepared. Tablets were prepared from spheroids, using conventional techniques. The tablets dissolve in under 10 minutes.

The spheroids were prepared by a wet granulation process followed by extrusion and spheronization, as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed drier and passed through a screen. The uncoated spheroids were stored in appropriate container.

EXAMPLE 3: PREPARATION OF TABLETS OF METHYLNALTREXONE

BROMIDE

Methylnaltrexone bromide can be prepared, for example, according to the methods described in detail in international PCT Patent Application publication numbers WO 2011/112816. Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, for example, colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc.

Spheroids containing methylnaltrexone were prepared. Tablets were prepared from spheroids, using conventional techniques.

The spheroids were prepared by a wet granulation process followed by extrusion and spheronization, as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed drier and passed through a screen. The uncoated spheroids were stored in appropriate container.

EXAMPLE 4: PREPARATION OF TABLETS OF METHYLNALTREXONE

BROMIDE

Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients using a direct compression technique. Methylnaltrexone and excipients are sieved, screened and dry blended. The blend is then weighed and compressed into tablets using standard procedures. A non-functional coating is then applied to the compressed tablets. Pharmaceutically acceptable excipients include, for example, colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscaraiellose sodium, poloxamer 407, siliconized microcrystalline cellulose and stearic acid. EXAMPLE 5: CLINICAL PHARMACOKINETICS OF ADMINISTERED METHYLNALTREXONE

Presented herein is a clinical pharmacokinetics study, Study C, as well as Studies A and B. Study A investigated the single and multiple dose pharmacokinetics of methylnaltrexone (MNTX) and its metabolites (M2: methylnaltrexone sulfate; M4: 6a- methylnaltrexol; and M5: 6P-methylnaltrexol) following the subcutaneous administration of 12 mg methylnaltrexone. In Study B, the single and multiple dose pharmacokinetics of methylnaltrexone (MNTX) and its metabolites (M2, M4, and M5) were examined following a 20- minute short intravenous infusion of 24 mg of methylnaltrexone (MNTX).

In Study C, the pharmacokinetics of methylnaltrexone (MNTX) and its 3 metabolites (M2, M4 and M5) were investigated in two stages: 1) single and multiple dose pharmacokinetics of MNTX and 3 metabolites, (M2, M4 and M5) following MNTX 450 mg PO x 7 days, and 2) the relative MNTX bioavailability following single oral dose administration of 450 mg MNTX as uncoated and film-coated 150-mg MNTX tablets (Example 3). In addition, the urinary elimination of MNTX was characterized.

Pharmacokinetic parameters included C_max, AUC_t, AU _nf, t_max, tm, Re₂₄, accumulation factor (R) as defined below and metabolite/parent drug ratio.

R = Accumulation Factor (based on AUCo-₂₄ (ng.h/mL): Day 7 AUC AUCo-₂₄ / Day

1 AUCo-₂₄

Metabolite-Parent Drug ratio (based on ng.h/mL) (%) =100 * (Metabolite

AUC₂₄/MNTX AUC₂₄)

Note: AU _nf was used in place of AUC AUCo-₂₄ for R and Metabolite-Parent Drug ratio computations following IV administration. Results are summarized in Tables 1 and 2.

Single and Multiple Dose Pharmacokinetics [Mean (SD)] of Methylnaltrexone (MNTX) and its metabolites of Study C;

Compared to Studies A and B as Noted

: data taken from Study B, a study of 24 mg given as a short infusion. : data taken from Study A, a study of 12 mg given sc.

Harmonic mean (harmonic SD) %Re= % dose excreted by renal route, R= AUC₀_₂₄ on Day 7/AUC₀_₂₄ on Dayl, %Re₂ = % oral dose excreted in urine in 24hr

Table 2: Single and Multiple Dose Pharmacokinetic Parameters [Mean (SD)] for Methylnaltrexone (MNTX) and its metabolites

(con ).

: data taken from Study B, a study of 24 mg given as a short infusion. : data taken from Study A,a study of 12 mg given as SC.

T_max = Median (Min, Max) * Harmonic mean (harmonic SD)

* Harmonic mean (Jackknife SD), R= AUCo-2 on Day 7/AUC₀-2 on Dayl, %Re₂4 = % oral dose excreted in urine in 24hr, NC= not computed

Tables 1 and 2 indicate that following oral and subcutaneous administrations, MNTX was readily absorbed with maximum MNTX plasma concentrations observed at 2 h and 0.25 h following oral dose and subcutaneous administration, respectively. Less than 4% of the orally administered dose was recovered in urine as an unconverted MNTX, markedly lower than the 31.5% - 49.6% recovered in in urine following IV administration (Yuan et al. 2005 J Clin Pharm 45:538-546). Cross-study AUQ_nf comparisons indicated that MNTX tablets demonstrated an absolute bioavailability of 4.24% (relative to IV infusion) and 3.7% bioavailability relative to SC injection whereas following multiple dose administration resulted in a slight increase in these values (higher AU _nf) of 4.8% and 5.8% relative to SC and IV multiple dose administrations. Subcutaneous MNTX injection resulted in high bioavailability (112%) relative to short-term infusion.

MNTX oral administration resulted in extensive metabolism, resulting in the formation methylnaltrexone sulfate (M2) and stereo specific hydroxylation to form 6a- (M4) and 6P-methylnaltrexol (M5) of which M4 was found to be the favored route of metabolite formation. Metabolic enzymes AKRC1C, SULT2A1 and SULT1E1 enzymes were reported be responsible for the MNTX metabolism into M2, M4 and M5.

No substantial differences in the average C_max and T_max were observed for MNTX and M2 between day 1 and day 7 for oral, SC or IV routes. These results indicate that the observed degree of accumulation (R) following multiple oral dose administration and reaching the apparent steady state was due to increased AUC values and decreased elimination which was evidenced by increased AU _nf and delayed elimination t_1/2 observed on Day 7 pharmacokinetics. Following subcutaneous administration, C_max and AUQ_nf for MNTX and its metabolites were similar between Day 1 and Day 7, whereas following oral administration of MNTX tablets considerable increase in AUC and C_max were observed on Day 7 for MNTX and its metabolites. Higher accumulation for MNTX and its metabolite following multiple dose oral administration was evident from higher accumulation factor (R) values following oral dose (1.20 for MNTX, 1.30 for M2, 1.62 for M4 and 1.76 for M5) compared with the R values following subcutaneous administration (1.05 for MNTX, 1.13 for M2, 1.25 for M4 and 1.42 for M5). Following oral administration of MNTX, metabolite to MNTX ratios were higher for all three metabolites: 81.0% for M2, 54.21% for M4, and 29.78% for M5, compared to the lower metabolite-MNTX ratios following subcutaneous administration (29.30% for M2, 18.75% for M4, and 8.72 % for M5). In Study C, relative bioavailability of two methylnaltrexone formulations (film coated tablet and uncoated tablet) was evaluated using methylnaltrexone plasma pharmacokinetics and 90% CI approach. Mean plasma concentration-time profiles and results presented in Table 3 indicated that film coated methylnaltrexone tablets resulted in LSM (least squares mean) ratio between 90-105%. Intra-subject variability for MNTX formulations was between 29-36%. ^■

Table 3: Relative Bioavailability of Two Methylnaltrexone (450 mg) tablets

Median (Min, Max) * Harmonic mean (harmonic SD)

EXAMPLE 6: CLINICAL PHARMACOKINETICS OF ORAL ADMINISTRATION OF METHYLNALTREXONE COMPARED TO SUBCUTANEOUS ADMINISTRATION OF THE SAME

The oral dosage levels and formulation of MNTX evaluated here were the same as those in a study of oral MNTX tablets, with the exception of a nonfunctional coating on the MNTX tablets. This nonfunctional coating is comprised of inactive ingredients polyvinyl alcohol, polyethylene glycol, and titanium dioxide. The pharmacokinetics of the uncoated tablet used in the study and the coated tablets used in the current study were compared in a separate study. The current study was designed to evaluate the comparative bioavailability of orally administered, 150, 300, and 450 mg MNTX doses versus a 12 mg subcutaneous (SC) injection of MNTX. A single-dose pharmacokinetic profile of oral MNTX tablets was also planned for evaluation in this study.

The objectives of this study were to evaluate the comparative bioavailability of 150, 300, and 450 mg single oral doses of MNTX tablets (Example 3) versus a 12 mg single SC dose of MNTX, and to characterize the pharmacokinetics of MNTX tablets after single oral dose administration in healthy subjects.

Presented herein is a randomized, open-label, crossover study consisting of 6 dosing sequences, each with 2 dosing periods; the dosing periods were separated by 7 days. All subjects were housed in the clinical research unit from Day -1 through Day 14 and were discharged on Day 15, which concluded their participation in the study. Prior to receiving study drug on Days 1 and 8, the subjects underwent an overnight fast of at least 10 hours, beginning on Days 0 and 7, respectively. In both dosing periods, the subjects received a single oral dose of MNTX tablets (150, 300, or 450 mg) or a single SC injection of MNTX (12 mg). The dosing was conducted in a crossover fashion (e.g., a tablet was administered at one visit and a SC injection was administered at the alternate visit). The strength of oral methylnaltrexone dose (150 mg, 300 mg, or 450 mg) and the dosing sequence (Dayl: oral tablet; Day 8: SC injection vs the alternate dosing order) for each subject were determined by random assignment. Each oral dose was administered with 240 mL of room temperature drinking water. The subjects were instructed to drink all of the water and were told to swallow the tablets whole (e.g., not to chew, divide, or crush them). Blood samples were collected for pharmacokinetic analyses prior to dosing (approximately 1 hour prior) on Day 1, and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing on Days 1 and 8.

Each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX. In addition, each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc.

Each injection vial contained 12 mg of the active pharmaceutical ingredient, MNTX, per 0.6 mL of solution (i.e., 20 mg/mL solution). The formulation also contained the following inactive ingredients: edetate calcium disodium, sodium chloride, glycine hydrochloride, and sodium hydroxide. In this study, all 48 enrolled subjects received study drug in each of the 2 study periods and were included in the safety and pharmacokinetic analyses.

The mean C_max for MNTX was observed at 15 minutes following 12 mg SC injection and plasma concentrations then diminished rapidly within the initial postdosing period (Table 26; abbreviations: PO = per oral, SC = subcutaneous). Beginning around 4 hours postdosing and continuing through at least 72 hours postdosing, there were greater mean plasma concentrations of MNTX following oral MNTX dosing relative to the SC injection for the 300 mg and 450 mg doses, but not for the 150 mg oral dose.

Single-dose pharmacokinetic parameters of SC MNTX compared with oral MNTX demonstrated that C_max was 4- to 13-fold higher, T_max was 6- to 8-fold shorter, and t_½ was shorter by 5 to 7 hours following SC MNTX 12 mg versus oral MNTX 150, 300, and 450 mg (Table 26).

Systemic exposure to MNTX as measured by C_max and AUC followed generally linear, dose-dependent trends among the oral doses (Table 26). Mean AUC and C_max values increased with increasing single oral doses of MNTX tablets from 150 mg to 450 mg; C_max increased from 13.2 to 39.9 ng/mL and AUCo_∞ increased from 106.9 to 373.3 ng^»h/mL at MNTX 150 mg and MNTX 450 mg, respectively. Median T_max values were constant, ranging from approximately 1.5 to 2.0 hours post dosing. The mean CL/F values were also similar across oral dosing groups. The mean t_½ increased slightly from 14.0 hours to 16.6 hours as the oral MNTX doses increased, respectively, from 150 mg to 450 mg.

The C_max occurred more rapidly following administration of the SC injection (median Tmax = 15 minutes) than following any of the oral study drug administrations (median T_max ranged from 1.5 to 2.0 hours) (Table 26).

Comparison of systemic exposure parameters (C_max and AUC) demonstrates at least 4-fold higher mean C_max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo-_∞ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg (Table 26). Mean C_max values were 174.0 ng/mL following SC MNTX 12 mg versus 26.2 and 39.9 ng/mL following oral MNTX 300 mg and 450 mg, respectively; and mean AUCo-_∞ values following SC MNTX 12 mg were 269.1 versus 231.2 and 373.3 ng^«h/mL following oral MNTX 300 mg and 450 mg, respectively.

Further, consistent with the observed differences in C_max and AUC between SC MNTX 12 mg and oral MNTX 450 mg, 300 mg, or 150 mg, elimination of MNTX was faster following SC versus oral administration (Table 26). The MNTX clearance rate (CL/F) was faster, 45698.7 versus 1664001.3 mL/h, and the t_½ value was shorter, 9.2 versus 16.6 hours, for SC MNTX 12 mg compared with oral MNTX 450 mg.

Single-Dose Pharmacokinetic Parameters for Oral MNTX (150, 300, and 450 mg) and Subcutaneous MNTX (12 mg)

Abbreviations: AUCo-_∞ = area under the plasma concentration versus time curve from time 0 (predose) to time infinity; AUCo = AUC from time 0 (predose) to the last quantifiable concentration-time point; C_max = maximum observed plasma concentration; CL/F = apparent oral clearance; MNTX = methylnaltrexone; SC = subcutaneous; = time to _^; t_½ = terminal or disposition half-life.

Note: Mean values are arithmetic means unless otherwise specified.

Expressed as harmonic means and pseudo standard deviation based on jackknife variance.

Oral MNTX 450 mg resulted in a C_max that was approximately 20% of the C_max from SC MNTX 12 mg and an AUC₀-_∞ that was approximately 123% of the AUC₀-_∞ from SC MNTX 12 mg; the geometric mean ratios of the oral tablet (test) to the SC injection (reference) were 20.0% for C_max and 123.2% for AUCo-_∞ (Table 5). The lower bound of the 90% confidence interval for C_max (4.3%) was well below 80% and the upper bound of the 90% confidence interval for AUCo-_∞ (150.7%) was greater than 125% indicating that both parameters were nonbioequivalent by the 80% to 125% rule.

Also, the C_max values were approximately 13% and 6% following oral MNTX 300 mg and 150 mg, respectively, of the C_max following SC MNTX 12 mg, and the AUCo-_∞ values following these oral doses were approximately 75% and 36%, respectively, of the AUCo-_∞ following SC MNTX 12 mg (geometric mean ratios in Table 27). The 90% confidence intervals of the C_max and AUCo-_∞ geometric mean ratios indicated nonbioequivalence of the 300 mg and 150 mg oral doses with SC MNTX 12 mg by the 80% to 125% rule (lower bounds of the 90% confidence intervals were < 80%).

The bioavailability of oral MNTX relative to SC MNTX, comparing arithmetic mean AUCo values for oral MNTX 450 mg to SC MNTX 12 mg, was 3.7% (normalized to dose in mg/kg [assuming mean of 81 kg body weight, based on subject mean demographics] by the following calculation: 373.3 ng^«h/mL/[450 mg/81 kg] ÷ 269.1 ng^«h/mL/[12 mg/81 kg] x 100). Dose-normalized bioavailability of oral MNTX relative to SC MNTX for the 300 mg and 150 mg doses were 3.4% and 3.2%, respectively.

Geometric Mean Ratios and 90% Confidence Intervals for Oral MNTX to SC MNTX Systemic Exposure Parameters (Pharmacokinetic Population)

Abbreviations: CI = confidence interval; GMR = geometric means ratio calculated as the tablet/injection x 100; LSM = least squares mean; MNTX = methylnaltrexone bromide; SC = subcutaneous.

Systemic exposure to MNTX as measured by C_max and AUC followed generally linear, dose-dependent trends among the oral doses. Mean AUC and C_max values increased with increasing single oral doses of MNTX tablets from 150 mg to 450 mg; C_max increased from 13.2 to 39.9 ng/mL and AUC₀__∞ increased from 106.9 to 373.3 ng-h/mL at MNTX 150 mg and MNTX 450 mg doses, respectively. The C_max occurred more rapidly following administration of the 12 mg SC MNTX injection (median T_max = 15 minutes) than following any of the oral study drug administrations (median T_max ranged from 1.5 to 2.0 hours).

Comparison of systemic exposure parameters (C_max and AUC) demonstrates 4- to 13- fold higher mean C_max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo-_∞ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg. Mean C_max values were 174.0 ng/mL following SC MNTX 12 mg versus 26.2 and 39.9 ng/mL following oral MNTX 300 mg and 450 mg, respectively; and mean AUCo-_∞ values were 269.1 following SC MNTX 12 mg versus 231.2 and 373.3 ng^»h/mL following oral MNTX 300 mg and 450 mg, respectively.

Calculation of the geometric mean ratios for oral MNTX tablets (test) relative to the SC MNTX injection (reference) indicated that the C_max from an oral MNTX 450 mg dose was approximately 20% of that observed for the 12 mg SC MNTX injection and the AUCo-_∞ from an oral MNTX 450 mg dose was approximately 123% of that observed from the 12 mg SC MNTX injection. Also, the C_max values were approximately 13% and 6% following oral MNTX 300 mg and 150 mg, respectively, of the C_max following SC MNTX 12 mg, and the AUCo-oo values were approximately 75% and 36% following these oral doses, respectively, of the AUCo-oo following SC MNTX 12 mg.

Consistent with the observed differences in C_max and AUC between the 12 mg SC MNTX injection and the oral MNTX 450 mg, 300 mg, and 150 mg doses, elimination of MNTX was faster following SC injection versus oral administration: the MNTX clearance rate (CL/F) was faster, 45698.7 versus 1664001.3 mL/h, and the t½ value was shorter, 9.2 versus 16.6 hours, for the 12 mg SC MNTX injection compared with the oral MNTX 450 mg dose.

The dose-normalized bioavailability of oral MNTX relative to SC MNTX injection, comparing arithmetic mean AUCo-_∞ values for an oral MNTX 450 mg, 300 mg, or 150 mg dose to the 12 mg SC MNTX injection, were 3.7%, 3.4%, and 3.2%, respectively.

This was a randomized, open-label, crossover study consisting of 6 dosing sequences, each with 2 dosing periods. In both dosing periods, the subjects received a single oral dose of MNTX tablets (150, 300, or 450 mg) or a single SC injection of MNTX (12 mg). The dosing was conducted in a crossover fashion (i.e., a tablet was administered at one visit and a SC injection was administered at the alternate visit). Forty-eight subjects were enrolled and 47 subjects (97.9%) completed the study; one subject discontinued due to personal reasons after receiving study drug in both study periods. The subjects received study drug in accordance with the randomization schedule; specifically, 16 subjects each received a single oral dose of 150, 300, and 450 mg MNTX tablets and all 48 subjects received a single 12 mg SC injection of MNTX.

Single-dose pharmacokinetic parameters of SC MNTX compared with oral MNTX demonstrated that C_max was 4- to 13-fold higher, T_max was 6- to 8-fold shorter, and t_½ was shorter by 5 to 7 hours following SC MNTX 12 mg versus oral MNTX 150, 300, and 450 mg.

Systemic exposure to MNTX as measured by C_max and AUC (both AUCi_ast and AUCo-oo) followed generally linear, dose-dependent trends among the oral doses.

Comparison of systemic exposure parameters (C_max and AUC) demonstrates at least 4-fold higher C_max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo-_∞ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg. The T_max was shorter following SC MNTX 12 mg (15 minutes) than following oral MNTX 150 mg 300 mg, or 450 mg, (2, 1.5, and 2 hours, respectively). Also, consistent with the observed differences in C_max and AUC, the t_½ value was shorter, 9.2 versus 16.6 hours, for SC MNTX 12 mg compared with oral MNTX 450 mg (t_1/2 were 14.2 and 14. 0 hours following oral MNTX 300 mg and 150 mg, respectively).

The single-dose pharmacokinetics of oral MNTX 150 mg tablet (ion-pairing) formulation was also studied in a recent study of healthy adults and in prior studies of subjects with noncancer pain and OIC and subjects on stable methadone maintenance. The single-dose pharmacokinetic parameters of oral MNTX were generally similar in the current study and in these other studies, although there were some quantitative differences in C_max and AUC in the current study and recent study of healthy adults when compared with prior studies of subjects with noncancer pain and OIC and of subjects on stable methadone maintenance.

Methylnaltrexone by SC injection was compared to MNTX administered orally in a pharmacokinetic study in subjects on stable methadone maintenance. The oral MNTX formulation was different in the current study than in the previous study, in which the oral formulations were enteric-coated granules in capsules and enteric-coated tablets. Although it is difficult to compare the current study and the previous study due to different oral MNTX formulations, the comparative pharmacokinetic profiles between SC dosing and oral dosing were similar between studies. Specifically, as in the current study, T_max was shorter, C_max was higher, and t was shorter following SC dosing compared with oral dosing; whereas differences in AUC values between SC and oral administrations were less pronounced than the differences in C_max, T_max, and t_1/2. Dose-normalized oral bioavailability relative to SC injection was 2.43% for enteric-coated capsules and 2.27% for enteric-coated tablets in the previous study, compared with 3.7% for the oral tablet (ion-pairing) formulation in the current study.

Oral doses of 150, 300, and 450 mg MNTX tablets and 12 mg MNTX SC injection and well tolerated in healthy volunteers who received 1 of the 3 oral doses of MNTX tablets as well as the SC injection of MNTX in this 2-period crossover study.

EXAMPLE 7: STRAINING AND STOOL CONSISTENCY SCORES IMPROVE AFTER SUBCUTANEOUS ADMINISTRATION OF METHYLNALTREXONE

A 48-week open-label safety study was conducted to evaluate the safety of subcutaneous administration of methylnaltrexone to subjects having chronic non-cancer pain and opioid- induced constipation. The study involved 1034 patients who were administered 12 mg of methylnaltrexone bromide once per day (QD), as needed. The patients were required to take at least one dose per week.

Patients who were administered methylnaltrexone demonstrated significant improvement from baseline over the course of the study in terms of straining and stool consistency (Bristol Stool Scale). See Figure 5. The effect was immediate and durable for both measures.

Alleviating the underlying cause of excessive straining or decreasing the frequency of straining may be of benefit. In a large National Health Study in post-menopausal women, it was observed that severe constipation was a statistically significant risk factor for cardiovascular events (Salmoirago-Blotcher et al. 2011. Am J Med. 124(8):714-723). Accordingly, in some embodiments, provided herein is a method of decreasing the risk of a cardiovascular event a subject suffering from opioid-induced constipation, comprising administering a composition comprising methylnaltrexone to the subject. In some embodiments, the methylnaltrexone is administered subcutaneously. In some embodiments, the methylnaltrexone is administered orally. In some embodiments, the subject is receiving opioids chronically. In some embodiments, administration of the composition results in a decrease of about one point in a bowel movement straining scale. In some embodiments, administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale). In some embodiments, the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks. The cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.

Administration of methylnaltrexone bromide also provided sustainable rapidity and durable efficacy of response during 48 weeks of treatment (Figure 6). In the long-term study, patients undergoing treatment with methylnaltrexone demonstrated significant improvements from baseline over the course of the study in terms of rapid response (e.g. rescue-free bowel movement within four hours of dosing) and weekly rescue-free bowel movements (e.g.≥ 3 rescue-free bowel movements per week).

Accordingly, embodiments are also directed to a method of treating constipation in a subject, comprising administering a composition comprising methylnaltrexone to the subject, wherein administration of the composition results in a rapid response. In some embodiments, administration of the composition results in a bowel movement within four hours of dosing. Embodiments are also directed to a method of treating constipation in a subject, comprising administering a composition comprising methylnaltrexone to the subject, wherein administration of the composition results in an improvement in the number of weekly rescue- free bowel movements. In some embodiments, administration of the composition results in at least three or more bowel movements per week. In the foregoing embodiments, the methylnaltrexone can be administered subcutaneously. In the foregoing embodiments, the methylnaltrexone can be administered orally. In the foregoing embodiments, the subject can be receiving opioids chronically. In the foregoing embodiments, the rapid response or improvement that results from administration of the composition can be observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks. EXAMPLE 8: CLINICAL DATA RELATED TO ADMINISTRATION OF METHYLNALTREXONE

In several studies involving subjects with post-operative ileus, methylnaltrexone bromide was administered intravenously at amounts up to 24 mg every 6 hours (Q6H). Blood pressure and pulse were evaluated among 1421 patients using measures for acute and long-term change from baseline, potentially clinically significant outliers, and repeated measures analyses incorporating changes relative to acute and chronic dosing.

Figure 7 provides a summary of mean pulse (beats per minute [bpm] and supine blood pressure (mm Hg) changes from baseline on Day 1 and Day 3 in the post-operative ileus studies. At high doses of methylnaltrexone (12 mg or 24 mg administered intravenously every 6 hours), only small increases in pulse and small decreases in supine systolic blood pressure and diastolic blood pressure were observed. The small increases in pulse may have been reflexive changes secondary to the small decreases in blood pressure. Mean changes from baseline were generally low, and there were no remarkable differences between the treated groups and placebo groups. There was also no apparent effect of dose on pulse or blood pressure. In conclusion, a lack of effect on hemodynamics was observed in subjects who were exposed to extremely high systemic exposures of methylnaltrexone; no substantial differences were observed between treatment and placebo groups.

Figure 8 provides a summary of outliers for pulse and blood pressure parameters over 10 days of observation in the post-operative ileus studies. At the individual patient level, there were no apparent differences from placebo in the incidence of potentially-clinically significant decreases or increases in pulse of blood pressure at the high doses evaluated in these studies.

Pulse and blood pressure changes following subcutaneous administration of methylnaltrexone bromide (12 mg every day (QD) or 12 mg every other day (QOD)) to patients taking opioids for chronic pain were also analyzed. During the double-blind treatment phase of a study evaluating the safety and efficacy of methylnaltrexone bromide in patients with chronic non-cancer pain and opioid-induced constipation, there were no consistent, clinically meaningful changes in supine pulse or blood pressure (Figure 9). In addition, a longitudinal analysis of these parameters also showed no effect of methylnaltrexone bromide.

In summary, administration of methylnaltrexone bromide resulted in mild vasodilatory properties at supratherapeutic doses. However, negligible to nonexistent changes in blood pressure and pulse were observed at therapeutic doses used in the treatment of opioid-induced constipation.

Furthermore, during the course of these studies, there was no indication of increased platelet aggregation in in vitro studies at either physiologic (0.6 μΜ) or supraphysiologic (612 μΜ) concentrations, nor was corrected QT (QTc) interval prolongation observed during early studies of methylnaltrexone, either at physiologic (0.15 mg/kg or 0.3 mg/kg) or at supraphysiologic (>0.5 mg/kg) concentrations. In addition, no metabolic changes were observed during long-term treatment (up to 48 weeks) with methylnaltrexone (Figure 10). The aggregate absence of such indications, which are surrogates typically associated with cardiovascular risk, are consistent with the absence of a clear mechanism for increased cardiovascular risk.

The event rate of myocardial infarctions (Mis) in a 48-week, open label safety trial involving subjects suffering from opioid-induced constipation with chronic non-cancer pain was consistent with expected event rates calculated from available published literature in chronic non-cancer pain patients taking opioids (Carman et al. 2011. Pharmacoepidemiol Drug 5a/20(7):754-762. Figure 11 illustrates the event rate per 100 person years of exposure for these two populations. This is a comparison of the absolute event rates for myocardial infarction starting with the rate obtained in the claims-based study by Carman and colleagues. The claims based study is used as a point of reference for this population with the event rate of 0.6 per 100 patient years highlighted in the upper right. Below the data for the claims based study is the combined data for study in which subjects having chronic non-cancer pain were administered methylnaltrexone, which is essentially what would be predicted in the population undergoing chronic opiate therapy. Accordingly, no increased risk of MI based on administration of methylnaltrexone was observed. In contrast, the event rate per 100 person years of exposure in subjects having chronic non-cancer pain who were administered alvimopan was elevated above placebo (2.0 vs. 0.60, data based on a clinical study involving administration of alvimopan, "GSK014"). Figure 20 illustrates a comparison of the time to event for MI in patients administered with alvimopan compared with that in patients administered with methylnaltrexone, which supports the safety of methylnaltrexone administration.

Finally, no major differences between placebo and treatment groups were observed in with respect to event rates of cardiac treatment emergent serious adverse events (Figure 12). The treatment groups include: (1) the population who were randomized to receive methylnaltrexone during double-blinded studies for post-operative ileus or for opioid-induced constipation (advanced illness or chronic non-cancer pain) and (2) the population involved in an open-label study of methylnaltrexone for opioid-induced constipation.

Figures 13 through 18 illustrate data from studies involving administration of methylnaltrexone in clinical studies that indicate that there are no apparent dose-dependent effects of methylnaltrexone on pulse or blood pressure. This was observed for subcutaneous doses up to 12 mg QOD and 12 mg QD as well as for intravenous doses up to 24 mg administered every 6 hours.

Accordingly, embodiments are directed to a method of administering methylnaltrexone to a subject in need thereof, wherein administration of methylnaltrexone does not elevate the risk of an adverse cardiovascular event. In some embodiments, the methylnaltrexone is administered subcutaneously. In some embodiments, the methylnaltrexone is administered orally. In some embodiments, the subject is receiving opioids chronically. In some embodiments, administration of the composition results a bowel movement within about 4 hours after dosing. In some embodiments, administration of the composition results in the subject having > 3 rescue-free bowel movements per week. In some embodiments, the improvement in weekly bowel movement rate is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks. The cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.

EXAMPLE 9: EFFICACY OF DIFFERENT ORAL FORMULATIONS

A study was conducted to evaluate the efficacy of two different oral formulations of methylnaltrexone tablets in subjects with opioid-induced constipation (OIC) and non-cancer pain. This was a phase lb, randomized, double-blind, placebo-controlled, parallel group, single-dose study to evaluate the laxation efficacy, pharmacokinetics (PK), and safety of two formulations of methylnaltrexone oral tablets. Eligible subjects were receiving oral or transdermal opioids daily for at least 30 days prior to Day -4. Subjects were prescribed a minimum opioid dose of 80 mg oral morphine equivalents (including methadone) per day for at least 14 days prior to Day -4 and for the duration of the study.

Subjects who had a history of reported opioid induced constipation entered the screening phase, where opioid induced constipation was confirmed. Constipation due to opioid use was confirmed during the screening phase (7 to 14 days) by the following definition: fewer than 3 rescue-free bowel movements (RFBMs) per week on average and RFBMs that were associated with 1 or more of the following: (i) a Bristol Stool Form Scale (BSS) type 1 or 2 (hard or lumpy stools) for at least 25% of the RFBMs. (ii) straining during at least 25% of the RFBMs, and/or (iii) a sensation of incomplete evacuation after at least 25% of the RFBMs.

A RFBM was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement. Upon completion of the screening phase and RFBM assessment, eligible subjects entered an open-label phase (Day -4) to determine if they responded to a 12 mg subcutaneous (SC) dose of methylnaltrexone. Each eligible subject received a 12 mg SC MNTX injection about 1 hour after taking his/her opioid dose. If the subject had a RFBM within 4 hours of the SC methylnaltrexone dose, they returned in 2 days and entered a 4-day in-patient double-blind treatment phase, followed by a 1-week follow-up phase. Responders entered the in-patient treatment phase and were randomized in a 1: 1: 1 ratio (minimum of 25 subjects per arm) to: (i) a single dose of Formulation A MNTX oral tablets (450 mg dose, 3 tablets), (ii) a single dose of Formulation B MNTX oral tablets (450 mg dose, 3 tablets), or (iii) placebo direct compression formulation oral tablets (3 tablets) as a single dose. Subjects were administered the study drug about 1 hour after taking the opioid dose and had fasted for at least 8 hours prior to study drug administration.

In Formulation A, each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX. In addition, each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, microcrystalline cellulose, siliconized microcrystalline cellulose, sodium lauryl sulfate, stearic acid, poloxamer 407, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and croscarmellose sodium. The tablets were made by a direct compression process. (Example 4)

In Formulation B, each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX. In addition, each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc. The tablets were made by a wet granulation process. (Example 3) Formulation B tablets had previously demonstrated safety and efficacy in clinical studies (Examples 1, 5 and 6).

Serial PK samples were collected prior to and for 4 hours following the single dose of open-label MNTX on Day -4 and prior to and for 24 hours following the single dose of study drug on Day 1. Opioid withdrawal was assessed using the following: (i) the Subjective Opiate Withdrawal Scale (SOWS) and (ii) the Clinical Opiate Withdrawal Scale (COWS). Subjects also underwent pupillometry. In addition, the question "Based on the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, did this subject experience opioid withdrawal?" was answered 'yes' or 'no' by a trained and blinded investigator familiar with opioid withdrawal symptoms. Safety and laxation effects were also assessed following dosing. Safety was assessed based on the incidence, intensity and types of adverse events (AE), changes in vital signs relative to baseline, changes in clinical laboratory parameters relative to baseline and presence or absence of opioid withdrawal indication.

One efficacy endpoint was clinical response, defined as the proportion of subjects who had a RFBM within 4 hours after a single oral dose of study drug (double-blind treatment phase). A RFBM was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement. Additional efficacy endpoints included: (i) clinical equivalence of Formulations A and B with regard to the primary efficacy endpoint, (ii) proportion of subjects with a RFBM within 24 hours after a single oral dose of the study drug, (iii) time to the first RFBM after a single oral dose of the study drug (censored after 24 hours post dose), (iv) stool consistency (Bristol Stool Form Scale), (v) straining, and (vi) sensation of complete evacuation The following pharmacokinetic parameters of methylnaltrexone and metabolites were assessed: (i) C_max (maximum observed plasma concentration), (ii) T_max (time to maximum observed plasma concentration), (iii) AUCo-t (area under the concentration versus time curve from time 0 (predose) to the last measurable concentration), (iv) AUCo-4 (area under the concentration versus time curve from time 0 (predose) to 4 hours after study drug administration). The following additional PK parameters were estimated for methylnaltrexone if adequate data were available: (i) AUCo-_∞ (area under the plasma concentration versus time curve from time 0 (pre-dose) extrapolated to time infinity, (ii) λζ (terminal phase rate constant), (iii) t½ (half-life), and (iv) apparent oral clearance (CL/F). The metabolite to parent ratio for C_max and AUCo-4 was calculated for each MNTX metabolite after SC and oral administration of MNTX. In addition, exploratory analyses was carried out to evaluate pharmacokinetic/pharmacodynamics relationships between methylnaltrexone systemic exposure and efficacy.

A total of 128 subjects were enrolled in the open-label phase of the study, and 120 of these subjects were responders to the SC MNTX injection and were eligible for the double- blind phase. Of these 120 responders, 111 entered the double-blind phase and completed the study. Demographics were generally comparable between double -blind treatment groups. Baseline characteristics were generally similar for subjects in in the open-label and double- blind treatment phases and by treatment group. For most subjects (76%), back pain was the primary condition requiring opioids (Table 8). The overall mean opioid morphine equivalent dose was 212.68 mg/day, and means were similar by study phase and treatment group (range: 204.88 to 220.00 mg/day).

The proportion of subjects with a RFBM within 4 hours after a single oral dose of study drug (efficacy endpoint, double-blind treatment phase), was 39.5% (15/38 subjects) for the Formulation A MNTX group, 37.8% (14/37 subjects) for the Formulation B MNTX group and 16.2% (3/37 subjects) for the placebo group. The increases in oral MNTX 450 mg endpoint results versus placebo (Δ) were statistically significant: 23.3% (p = 0.0249) for the Formulation A group and 21.6% (p = 0.0363) for the Formulation B group. See Figure 27. Clinical equivalence in efficacy endpoint results was demonstrated between the Formulation A MNTX group and the Formulation B MNTX group (Table 6). The 90% confidence interval (CI) for the difference in clinical response rate between the Formulation A group and the Formulation B group was -17%, 20%; this 90% CI was within the protocol-defined interval of -20%, 20% (-0.20; +0.20) , which demonstrated the clinical equivalence of the two oral MNTX formulations.

Table 6. Clinical Equivalence: Difference between oral methylnaltrexone formulations in endpoint results (double-blind treatment phase)

Formulation Formulation

A MNTX B MNTX

Placebo 450mg 450 mg

(n = 37) (n = 38) (n = 37)

Subjects with a RFBM within 4 hours after 6 (16.2) 15 (39.5) 14 (37.8) the single dose of studv drug in the double-

Percent difference vs placebo (Δ) 23.3 21.6

P- value versus placebo 0.0249 0.0363

90% CI for % Difference. (Formulation A

vs Formulation B)

Abbreviations: MNTX = methylnaltrexone; RFBM = rescue-free bowel movement. Notes: Rescue-free bowel movement was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement.

There were significant improvements versus placebo (p < 0.05) in the Formulation A MNTX group and the Formulation B MNTX group in stool consistency and straining (Table 7). Results for the change from screening assessment to the assessment after the double-blind dose of study drug showed significant (p < 0.05) improvements for each oral formulation MNTX group compared with placebo for the following: average BSS score of RFBMs, average straining scales score of RFBMs, and percentage of RFBMs with straining scores of 0 or 1.

Table 7. Changes from Baseline in Stool Consistency and Straining

Formulation Formulation B

A MNTX MNTX

Placebo 450mg 450 mg

(n = 37)^a (n = 38)^a (n = 37)^a

Change from screening in average BSS score of RFBMs^b

Mean (SD) -0.21 (2.056) 0.79 (2.374) 0.90 (1.938)

Median (min, max) -0.50 (-4.3, 1.17 (-5.0, 1.00 (-4.5,-4.5)

Treatment Comparison⁶

At 25th percentile of the baseline

LS Means 0.62 2.19 1.56

LS Mean Differences (vs 1.57 0.94

Placebo)

P-value (vs Placebo) 0.0067 0.1082

At 50th percentile of the baseline

LS Means -0.03 0.89 0.88

LS Mean Differences (vs 0.92 0.90

Placebo)

P-value (vs Placebo) 0.0345 0.0374

At 75th percentile of the baseline

LS Means -0.16 0.63 0.74

LS Mean Differences (vs 0.79 0.90

Placebo)

P-value (vs Placebo) 0.0665 0.0395

Change from screening in average straining scale score of RFBMs ^c

Mean (SD) 0.50 (2.019) -0.30 (2.020) -0.61 (2.018)

Median (min, max) 0.25 (-3.7, -0.38 (-3.0, -1.0 (3.0, 4.0)

Treatment Comparison^g

LS Means 0.55 -0.34 -0.62

LS Mean Differences (vs Placebo) -0.89 -1.17

P-value (vs Placebo) 0.0353 0.0062

Change from screening in percentage of RFBMs with straining score of 0 or l^d

Mean (SD) 0.16 (0.508) 0.37 (0.540) 0.31 (0.583)

Median (min, max) 0.0 (-1.0, 1.0) 0.8 (-0.8, 0.0 (-1.0, 1.0) Treatment Comparison⁶

LS Means 0.12 0.38 0.35 LS Mean Differences (vs Placebo) 0.26 0.23

P- value (vs Placebo) 0.0192 0.0369

Abbreviations: DB = Double-Blind; MNTX = methylnaltrexone; RFBM = Rescue Free Bowel Movement.

Note: RFBM was a bowel movement without laxative use within 24 hours prior to the bowel movement.

a. Screening and double -blind assessments were recorded for 36 subjects in each treatment group.

b. Stool consistency score is considered zero for subjects with no RFBM during the DB phase.

c. Straining score is considered 5 (very severe) for subjects with no RFBMs during the DB phase.

d. Percentage was calculated as the number of RFBMs with straining score of 0 (none) or 1 (mild)/total

number of RFBMs. The percentage was considered zero for subjects with no RFBMs during the DB phase. e. Least Square (LS) means, LS mean difference, and p-value were obtained from a linear regression model comparing the change from baseline between treatment groups adjusting for baseline and baseline by treatment interaction. The interaction term was dropped from the model if it was found not significant (p>0.10). If the interaction term was significant, treatment difference were estimated and tested at 25th, 50th and 75th percentiles of baseline value.

The proportion of subjects with any diarrhea or watery RFBMs (BSS Type 6 or 7) was similar for all 3 treatment groups (placebo 2.8%; Formulation A MNTX 2.8%, and Formulation B MNTX 5.6%), with no significant differences between each MNTX formulation and placebo.

Mean C_max was approximately 4-fold greater following SC MNTX (132.82 ng/mL) than following oral MNTX from each tablet formulation (Formulation A: 34.58 ng/mL; Formulation B: 35.35 ng/mL). Also, median T_max was 4- to 6-fold shorter following SC MNTX (0.35 hour) as compared with each oral tablet formulation (Formulation A: 1.53 hours; Formulation B: 2.00 hours) (Table 8). Statistical analyses comparisons (analysis of variance) of PK following oral dosing indicate that mean C_max and mean AUCo-_∞ were not different between the two oral MNTX formulations (Formulation A versus Formulation B; p > 0.05).

Table 8. Mean (+ SD) plasma methylnaltrexone (MNTX) pharmacokinetic parameters following single MNTX 12 mg SC injection and single MNTX 450 mg oral tablet doses

(Formulation A or Formulation B)

Abbreviations: AUCo-t = area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma concentration-time point; AUCo-4 = AUC from time 0 (predose) to 4 hours post-dose; AUCo-oo = AUC from time 0 (predose) to time infinity; CL/F = apparent oral clearance; C_max = maximum observed plasma concentration; MNTX = methylnaltrexone; NC = not calculated; SD = standard deviation; max = time to C_max.

a Reported as median (range).

b Expressed as harmonic mean and pseudo standard deviation based on jackknife variance.

c C_max and AUCo-_∞ were compared between oral MNTX formulations by using analysis of variance.

Systemic exposure parameters, C_max and AUCo-4, for the MNTX metabolites methylnaltrexone sulfate (M2), methyl-6a-naltrexol (M4), and methyl-6P-naltrexol (M5), were greater following oral administration compared with SC administration, as were the metabolite to parent ratios for C_max and AUCo-4 for each of the three MNTX metabolites (Table 9). For AUCo-4, mean metabolite to parent ratios following oral administration were approximately 3- to 4-fold greater compared with SC administration for each of the 3 metabolites. For C_max, the mean metabolite to parent ratios were approximately 8- to 9-fold greater for methylnaltrexone sulfate following oral administration compared with SC administration, and approximately 6- to 8-fold greater for methyl-6a-naltrexol and methyl- ββ-naltrexol following oral administration compared with SC administration.

Table 9. Mean (+ SD) plasma methylnaltrexone (MNTX) metabolites pharmacokinetic parameters following single MNTX 12 mg SC injection and single MNTX 450 mg oral tablet doses (Formulation A or Formulation B)

Open-label Double-blind

Subcutaneous Formulation A Formulation B

MNTX 12 mg MNTX 450 mg MNTX 450 mg

Parameters (N=72) (N=37) (N=36)

Methylnaltrexone sulfate (M2)

C_max (ng/mL) 9.22 (6.398) 17.72 (15.323) 19.35 (14.970)

T_max ^a (hours) 4.00 (0.50, 4.05) 5.95 (0.50, 8.23) 6.00 (2.0, 12.2)

AUCo-t (ng.h/mL) 21. 40 (14.454) 218.35 (221.862) 242.56 (200.623)

AUCo-4 (ng.h/mL) 22.07 (14.454) 29.19 (28.139) 32.90 (26.876)

Ratio of AUCo-4 0.117 (0.071) 0.45 (0.430) 0.43 (0.323)

Ratio of C_max 0.09 (0.087) 0.75 (0.692) 0.70 (0.444)

Methyl-6a-naltrexol (M4)

Cmax (ng/mL) 3.55 (2.587) 4.62 (2.818) 6.54 (7.373)

Tmax ³ (hours) 1.50 (0.50, 4.05) 2.02 (0.50, 7.85) 3.92 (0.70, 6.23)

AUCo-t (ng.h/mL) 10.00 (7.075) 44.95 (25.353) 64.13 (70.785)

AUCo-4 (ng.h/mL) 10.28 (7.140) 12.19 (8.070) 17.90 (22.035)

Ratio of AUCo-4 0.05 (0.027) 0.17 (0.080) 0.19 (0.113)

Ratio Of Cmax 0.03 (0.017) 0.17 (0.092) 0.20 (0.127)

Methyl-6p-naltrexol (M5)

Cmax (ng/mL) 1.20 (0.906) 1.95 (1.150) 2.56 (2.818)

Tmax ³ (hours) 2.00 (0.5, 4.0) 4.00 (0.5, 8.2) 4.0 (0.75, 8.2)

AUCo-t (ng.h/mL) 3.52 (2.694) 23.90 (13.798) 31.22 (34.252)

AUCo-4 (ng.h/mL) 3.63 (2.745) 4.81 (3.521) 6.59 (7.663)

Ratio of AUCo-4 0.02 (0.010) 0.06 (0.030) 0.07 (0.040)

Ratio Of Cmax 0.01 (0.008) 0.08 (0.052) 0.08 (0.053)

Abbreviations: AUCo-t = area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma concentration-time point; AUCo-4 = AUC from time 0 (predose) to 4 hours post-dose; AUCo-_∞ = AUC from time 0 (predose) to time infinity; CL/F = apparent oral clearance; C_max = maximum observed plasma concentration; MNTX = methylnaltrexone; NC = not calculated; SD = standard deviation; T_max = time to maxj

Note: Ratios of AUCo-4 and C_max represent the metabolite to parent ratios,

a Reported as median (range).

b Expressed as harmonic mean and pseudo standard deviation based on jacknife The differential metabolite exposure after oral administration is not anticipated to affect the safety or efficacy of orally-administered MNTX.

Overall, safety results for Formulation A and Formulation B of MNTX were similar to placebo. In the open-label period, 15 of 128 subjects (12%) experienced treatment- emergent adverse events (TEAEs) following the single 12 mg SC dose of MNTX on Day -4. Most events were mild in severity with 2 subjects experiencing moderate events (abdominal pain upper and headache). In the double-blind period, 26 of 112 subjects (23%) experienced TEAEs. Most events were mild in intensity. There were no serious adverse events (SAEs) or deaths during the study, and no subject discontinued the study early due to a TEAE.

No clinically significant changes in laboratory test results, or vital signs, were observed during the study. There were minimal mean changes from baseline to last assessment in hematology, chemistry and urinalysis, and the changes from baseline were not clinically significant. In addition, there were minimal changes from baseline to endpoint in urinalysis characteristics.

There were no notable differences in opioid withdrawal assessment between placebo and oral MNTX groups. All subjects had severity grades of none or mild for COWS and SOWS scores during the double-blind period, and there were no notable differences among placebo and oral MNTX groups in the percentages of subjects by COWS and SOWS severity grades. No subject in the oral MNTX treatment groups experienced opioid withdrawal based on the DSM-5 criteria as determined by the investigator at postbaseline time points. Slight decreases from baseline to postbaseline time points in pupil size were observed, but these changes from baseline were similar between placebo and oral MNTX treatment groups; thereby indicating no reversal of opioid-induced miosis resulting from oral MNTX treatment.

The results of this study demonstrate that a 450-mg dose of Formulation A MNTX was effective and had clinically equivalent efficacy to Formulation B MNTX. The safety profile of each formulation was similar to placebo. Results of serial collection of several opioid withdrawal measurements, at time points that include the T_max for plasma MNTX, indicate that oral MNTX 450 mg had minimal effects that were comparable to placebo on opioid withdrawal symptoms during the study. PK parameters describing systemic exposure of MNTX were not statistically different between Formulation B MNTX and Formulation A MNTX. EXAMPLE 10: FOOD EFFECT OF AN ORAL FORMULATION

A phase 1, two-arm, randomized, open-label, crossover study was carried out to evaluate the pharmacokinetics of a single oral dose of methylnaltrexone tablets (Formulation B, Example 3) after a high-fat meal or after fasting in healthy subjects.

Subjects were randomized at a 1: 1 ratio to Arm 1 (fasted then fed) or Arm 2 (fed then fasted). Each subject received a single oral dose of 450 mg (3 x 150 mg tablets) MNTX (Formulation A) with a high fat meal (MNTX fed) and after fasting (MNTX fasted). The fasted/fed study periods were separated by 6 days. The sequence of fasted/fed or fed/fasted dosing on Days 1 and 8 were determined by randomization on Day 1. Blood samples for PK analyses of MNTX were collected predose and up to 96 hours postdose following both fasted and fed single-dose treatment administrations. Plasma concentrations of MNTX were determined by a validated LC/MS/MS assay with a LLOQ of 0.05 ng/mL.

Administration of a single, 450 mg dose of MNTX to healthy subjects under fed conditions resulted in a substantial decrease in systemic exposure when compared to MNTX administration under fasted conditions (Table lOError! Reference source not found.)- Both AUCo and C_max decreased by approximately 47% and 64%, respectively, after administration with a high-fat meal relative to administration in the fasted state. Median T_max was delayed in the fed state when compared with the fasted state (4.0 hours versus 2.0 hours, respectively). Mean MNTX t_½ was similar when administered with or without food (approximately 14 hours for each), indicating that administration with food does not affect the systemic disposition of MNTX.

Table 10. Mean (±SD) plasma pharmacokinetic parameters of a 450 mg dose of methylnaltrexone: Food effect

Single-Dose Fasted Single-Dose Fed

Parameters N = 32 N = 32

Cmax (ng/mL) 42.53 (32.356) 15.08 (5.764)

Tmax (h) ³ 2.00 (0.25, 4.00) 3.99 (1.00, 6.04)

AUq_ast (ng.h/mL) 302.69 (147.706) 161.061 (32.354)

AUCo-oo (ng.h/mL) 305.91 (147.932) 164.059 (34.557)

CL/F (L/h) 1744.35 (657.173) 2867.44 (628.238) λ_ζ (h^"1) 0.049 (0.011) 0.049 (0.014) t_½ (h) ^b 14.17 (3.253) 14.15 (4.044)

Abbreviations: AUCi_ast= area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma concentration-time point; AUCo-_∞ = AUC from time 0 (predose) to time infinity; CL/F = apparent oral clearance; C_max = maximum observed plasma concentration; t_1/2 = half-life; MNTX = methylnaltrexone; SD = standard deviation; T_max = time to C_max; λ_ζ= termination elimination constant

a Median (range).

b Harmonic mean (pseudo SD based on jackknife variance).

Thirteen of 32 subjects (41%) experienced TEAEs during the study; 11 subjects (34%) during the fasted dosing period and 6 subjects (19%) during the fed dosing period. All TEAEs were considered mild or moderate by the investigator. Ten subjects (31%) experienced TEAEs that were considered by the investigator to be related to MNTX. There were no deaths, SAEs, or TEAEs resulting in study discontinuation.

The results of this study demonstrate that administration of oral MNTX with food decreases both the rate and extent of MNTX oral absorption. Therefore, oral MNTX should be administered in the fasted state. Although fasting resulted in increased systemic exposure to MNTX, the incidences of TEAEs considered treatment related were similar between fed and fasted conditions. A single dose of MNTX 450 mg was well-tolerated.

Accordingly, embodiments are directed to the methods of administering methylnaltrexone to a subject, wherein the methylnaltrexone is provided in an oral pharmaceutical composition, and wherein the composition is administered to a subject without food (or on an empty stomach). In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 10 hours. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 9 hours. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 8 hours. In some embodiments administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6 hours. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 1 hour. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 2 hours. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 3 hours.

EXAMPLE 11: EFFECT OF HEPATIC IMPAIRMENT ON DOSING

Hepatic impairment can result in increased intestinal permeability as well as reduced first-pass metabolic clearance for orally- administered drugs. A phase 1, open-label study was conducted to evaluate the single-dose pharmacokinetics (PK) of oral methylnaltrexone (MNTX) tablets (Example 4) in subjects with hepatic impairment and in healthy subjects. In addition, the safety of a single dose of oral methylnaltrexone tablets was evaluated in subjects with hepatic impairment and in healthy subjects.

Hepatic impairment in the study was measured by Child-Pugh classification. The Child-Pugh classification system for the severity of liver disease is listed below (Table 11). The classification system determines severity of liver disease according to the degree of ascites (via clinical assessment), the plasma concentrations of bilirubin and albumin, the International Normalized Ratio, and the degree of encephalopathy.

Table 11. Child-Pugh Scoring System

Encephalopathy is classified as Grade 0-4 using the Conn scoring system provided as follows:

• Grade 0 = No personality or behavioral abnormality detected. • Grade 1 = Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of addition or subtraction.

• Grade 2 = Lethargy; disorientation for time; obvious personality change; inappropriate behavior.

• Grade 3 = Somnolence to semi-stupor, responsive to stimuli; confused; gross disorientation; bizarre behavior.

• Grade 4 = Coma; unable to test mental state.

A total score of 5-6 is considered Child- Pugh grade A (well-compensated disease); 7- 9 is Child Pugh grade B (significant functional compromise); and 10-15 is Child-Pugh grade C (decompensated disease).

Eligible subjects completed a screening period of up to 21 days, followed by a 5-day treatment period. Following the screening period, subjects checked in at the clinical research unit (CRU) on Day -1 and remained in the CRU through the 96-hour blood sample collection on Day 5. A follow-up phone call occurred 3 (+1) days after discharge from the CRU.

Subjects received a single 450-mg oral dose of MNTX (3 x 150 mg tablets, Formulation A) on Day 1 following an overnight (at least 8 hour) fast. Subjects continued to fast for 4 hours postdose with no water for 1 hour predose and 1 hour postdose (excepting water consumed with dose administration). Following the MNTX dose, blood samples for PK analysis of MNTX and metabolites were collected predose (within 1 hour prior to the dose) and through 96 hours postdose at various time points. Complete urine output was collected over the intervals of 0 - 4, 4 - 8, 8 - 12, 12 - 24, 24 - 48, 48 - 72, and 72 - 96 hours after administration of MNTX.

In Formulation A, each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX. In addition, each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, microcrystalline cellulose, siliconized microcrystalline cellulose, sodium lauryl sulfate, stearic acid, poloxamer 407, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and croscarmellose sodium. The tablets were made by a direct compression process.

A minimum number of patients having hepatic impairment were enrolled. This included at least 6 Child-Pugh A and 6 Child-Pugh B subjects as well as 6 healthy subjects. In addition to the minimum number of hepatic impairment subjects required by the protocol (6 Child-Pugh A and 6 Child-Pugh B), a cohort of subjects with severe hepatic impairment (Child-Pugh C) was evaluated, thereby placing total enrollment in the study at 24 subjects. Subjects excluded from the study included those who had consumed foods that are known to inhibit and/or induce cytochrome P450 enzymes (CYPs) (e.g., grapefruit juice, grapefruits, Seville [bitter] oranges, pomelos, pomelo juice, star fruit, broccoli, Brussels sprouts, or chargrilled meats) within 14 days of Day 1. In subjects with hepatic impairment, stable pharmacotherapy could be continued according to the normal schedule of administration, except for the following exclusions: (i) non-study MNTX within 14 days prior to Day 1, (ii) opioid agonists, partial opioid agonists (e.g., buprenorphine), non-study opioid antagonists, or combination agonists/antagonists within 14 days prior to Day 1 and throughout the study, and/or (iii) lactulose or over-the-counter laxatives for 24 hours prior to and 48 hours following the MNTX dose.

Plasma PK parameters calculated for MNTX and metabolites (MNTX sulfate [M2], methyl-6a-naltrexol [M4], and methyl-6P-naltrexol [M5]), if measurable, included: (i) maximum observed plasma concentration (C_max), (ii) time of C_max (T_max), (iii) lag time of appearance in plasma (Ti_ag), (iv) area under the plasma concentration-time curve (AUC) from time 0 (predose) to 24 hours (AUCo-24), and (v) AUC from time 0 (predose) to last measured time point (AUCi_ast).

If sufficient plasma concentration-time data were available, the following PK parameters were calculated: (i) AUC to infinity (AUCI P), (ii) AUC extrapolated beyond last measured time point, (iii) Terminal phase rate constant (λζ), (iv) terminal half-life (ti/2), (v) apparent oral volume of distribution (V/F) of MNTX, and (vi) apparent oral clearance (CL/F) of MNTX.

Urine pharmacokinetic parameters calculated for MNTX, if measurable, included: (i) amount excreted in urine (A_eu) and (ii) renal clearance (CLR).

The safety endpoints were as follows: (i) incidence of treatment-emergent adverse events (TEAEs), (ii) changes from baseline in clinical laboratory assessments, (iii) changes from baseline in vital signs. Clinical laboratory parameters that were assessed included hematology, standard blood chemistry, serum cystatin C, coagulation and urinalysis. Vital signs that were measured included seated blood pressure (mm Hg), pulse (beats per minute) and oral temperature (°C).

Analysis populations included the PK Population (subjects from whom sufficient data were obtained for calculation of MNTX plasma PK parameters) and the safety population (subjects who received any study medication were included in the overall safety evaluation. Pharmacokinetic parameters for MNTX and its metabolites (M2, M4, and M5) were determined by standard model-independent methods. MNTX and metabolite concentrations were summarized for each collection time point or collection interval by the number of subjects evaluated (N), arithmetic mean, SD, coefficient of variation, median, minimum, and maximum. PK parameters for MNTX, M2, M4, and M5 were summarized for each hepatic impairment group by the number of subjects evaluated (N), arithmetic mean, SD, geometric mean, 95% confidence interval (CI), coefficient of variation, median, minimum, and maximum. The geometric mean ratio (hepatic impairment/healthy) and associated 90% CI for C_max, AUCiast, AUCo-24, and AUCo-_∞ for each hepatic impairment group was calculated. Additionally, the effect of hepatic impairment on the PK of MNTX was assessed based on the clinical relevance of PK changes and the relationships between PK and safety.

Safety analyses were descriptive and evaluations were based on the incidence, intensity and types of treatment-emergent AEs, and changes in clinical laboratory results and vital signs.

Of the total of 24 subjects who were enrolled; six subjects were randomized to each treatment cohort. Twenty-three subjects (96%) completed the study; one subject in the Child- Pugh C discontinued the study due to a TEAE considered not related to study drug. The enrolled subjects were 24 to 66 years of age; the mean age of healthy subjects (37 years) was lower than that of subjects with hepatic impairment (mean range: 51 to 59 years). Subjects were primarily male (71%), white (92%), and of Hispanic or Latino ethnicity (75%). Overall, subjects had a mean BMI of 29.6 kg/m 2. In healthy subjects, mean BMI was 26.9 kg/m 2 in healthy subjects; it ranged from 29.5 to 36.3 kg/m in subjects with hepatic impairment.

Mean linear and logarithmic plasma concentration-time profiles for MNTX and its metabolites (M2, M4, and M5) following a single 450 mg oral dose of MNTX are shown in Figures 28-31 (linear plots) and Figures 32-25 (logarithmic plots).

Summary pharmacokinetic parameters for MNTX and its metabolites following single 450-mg oral doses of MNTX (3 x 150 mg tablets) are presented in Tables 12 through 14. Table 12. Mean (+ SD) Plasma PK Parameters for MNTX Following a Single 450-mg Oral Dose (3 x 150 mg Tablets) to Healthy Subjects and Subjects with Hepatic Impairment

Abbreviations: AUCi_ast= area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma

concentration-time point; AUCo-24 = AUC from time 0 (predose) to 24 hours post-dose; AUCo__∞ = AUC from time 0 (predose) to time infinity; %AUC = Extrapolation percentage of AUC extrapolated beyond last measured time point to determine AUCo__∞; CL/F = apparent oral clearance; C_max = maximum observed plasma concentration; ti/2 = half-life; MNTX = methylnaltrexone; SD = standard deviation; Ti_ag = lag time preceding absorption; T_max = time to C_max; λ_ζ= termination elimination constant; V/F apparent oral volume of distribution a Reported as median (range).

b Expressed as harmonic mean and pseudo SD based on jackknife variance.

Table 13. Mean (+ SD) Plasma PK Parameters for MNTX Metabolites M2 and M4 Following a Single 450-mg Oral Dose (3 x 150 mg Tablets)

Healthy Subjects

Parameters (N=6) Child-Pugh A (N=6) Child-Pugh B (N=6) Child-Pugh C (N=6)

MNTX Sulfate (M2)

Cmax (ng/mL) 22.04 (9.924) 20.57 (18.446) 34.83 (26.803) 12.66 (11.628)

T_max ^a (h) 7.00 (3.0 - 8.0) 5.00 (4.0 - 6.0) 6.0 (3.0 - 8.0) 6.0 (6.0 - 6.0)

AUC₀-24 (ng.h/mL) 247.40 (109.948) 220.03 (176.251) 392.18 (356.198) 151.638 (122.193)

AUCi_ast (ng.h/mL) 265.71 (117.050) 244.59 (179.372) 457.33 (492.360) 166.16 (151.589)

AUC₀-_∞ (ng.h/mL) 272.40 (130.613) 255.93 (174.970) 466.70(492.709) 222.01 (152.459) λζ ίΐ ^"1) 0.0985 (0.0228) 0.1155 (0.0484) 0.1306 (0.0479) 0.0860 (0.0621) ti 2 (h) 7.04 (1.655) 6.00 (2.350) 5.31 (1.904) 8.06 (6.847)

Methyl-6 a-naltrexol

Abbreviations: Same as in Table 11

a Reported as median (range).

b Expressed as harmonic mean and pseudo SD based on jackknife variance.

Table 14. Mean (+ SD) Plasma PK Parameters for MNTX Metabolite M5 Following a Single 450-mg Oral Dose (3 x 150 mg Tablets) to Healthy Subjects and Subjects with Hepatic Impairment

Healthy Subjects

Parameters (N=6) Child-Pugh A (N=6) Child-Pugh B (N=6) Child-Pugh C (N=6)

Methyl-6P-naltrexol

(M5)

Abbreviations: Same as in Table 11

a Reported as median (range).

b Expressed as harmonic mean and pseudo SD based on jackknife variance.

Overall, administration of a single, 450 mg dose of MNTX to subjects with varying degrees of hepatic impairment (Child-Pugh A, B, or C) resulted in increased systemic exposure when compared to MNTX administration to healthy subjects. The mean C_max in subjects with Child-Pugh A hepatic impairment was approximately 1.8-fold higher than that of healthy subjects; in Child-Pugh B and C subjects, C_max was approximately 4.8- and 3.7- fold higher, respectively. Systemic exposure, as measured by AUCo-∞, was similar between healthy subjects and Child-Pugh A subjects (437 ng.h/mL versus 393 ng.h/mL, respectively), and was 2.5- and 2-fold higher, respectively, in Child-Pugh B and C subjects as compared to healthy subjects.

Median T_max was shorter in liver impairment subjects (median T_max ranging from 1 to 1.25 hours) when compared to healthy subjects (2.5 hours). Oral clearance (CL/F) values were lower in Child-Pugh B (700 L/h) and Child-Pugh C (661 L/h) subjects as compared with healthy subjects (1228 L/h) and Child-Pugh A subjects (1564 L/h). Mean t_½ of MNTX was 16 hours for healthy subjects, and was largely similar for subjects with hepatic impairment (Child-Pugh A: 19 hours, Child-Pugh B: 15 hours, Child-Pugh C: 17 hours).

In subjects with hepatic impairment, plasma concentrations of the metabolites M4 and M5 were lower compared with healthy subjects, as were PK parameters reflecting their systemic exposure For MNTX sulfate, healthy subjects and Child-Pugh A subjects demonstrated comparable exposure; Child-Pugh B subjects had greater systemic exposure to this metabolite than healthy subjects, while exposure in Child-Pugh C subjects was lower.

Table 15 presents results of statistical evaluations of systemic exposure after single 450-mg oral doses of MNTX in healthy subjects (reference) and those with Child-Pugh A, B, or C hepatic impairment (test) conditions. For C_max, AUCo-24, AUCi_ast, and AUCo-∞, the 90% CIs the geometric mean ratios of these parameters for healthy subjects versus those with hepatic impairment were outside of the range of 80% to 125%, indicating non-equivalent exposure in subjects with liver dysfunction. Consistent with these data, the 90% CIs for C_max, AUCo-24, UCiast, and AUCo-∞ for the metabolites of MNTX were outside of the range of 80% to 125% when compared with healthy subjects, indicating statistical non- bioequivalent systemic exposure. Table 15. Geometric Least Squares Mean and Geometric Mean Ratios (Hepatic Impairment:Healthy) and 90% CIs for MNTX C_max and AUC After Single Doses of MNTX

Abbreviations: AUCi_ast= area under the plasma concentration versus time curve from

time 0 (predose) to the last quantifiable plasma concentration-time point; AUCo-24 = AUC from time 0 (predose) to 24 hours post-dose; AUCo__∞ = AUC from time 0

(predose) to time infinity; C_max= maximum observed plasma concentration; LS = least squared.

Table 16 illustrates methylnaltrexone urine concentrations. The mean amount of MNTX excreted was slightly lower in Child-Pugh A subjects (6606 μg) than healthy subjects (8066 μg), but was markedly higher in Child-Pugh B (12648 μg) and Child-Pugh C subjects (16879 μg). Renal clearance rates were comparable for healthy subjects (306 mL/min), Child-Pugh A subjects (289 mL/min), and Child-Pugh C subjects (315 mL/min) and was slightly lower for Child-Pugh B subjects (244 mL/min). Renal clearance rates did not directly correlate to the MNTX concentration in urine. Table 16. Summary of Urine Concentrations of MNTX

Two subjects experienced a total of 3 treatment-emergent adverse events (TEAEs), none of which were considered related to MNTX. No deaths occurred during the study. Minimal changes in laboratory test results were observed for subjects during the course of the study. No laboratory test result was considered by the investigator to be a TEAE. No significant effect of MNTX on physical exam findings, cardiac safety parameters or vital signs was observed in this trial.

In conclusion, statistical evaluations of PK parameters after single doses of MNTX 450 mg, when administered to healthy subjects (reference) and those with Child-Pugh A, B, or C hepatic impairment (test), indicated non-equivalent exposure in subjects with liver dysfunction. Mean C_max values in Child-Pugh B and C subjects were approximately 4-and 5- fold higher, respectively, than healthy subjects, while C_max was 2-fold higher in Child-Pugh A subjects. Similarly, mean AUCo-∞ values were twice as high for Child-Pugh B and C subjects, compared with healthy subjects, while Child-Pugh A subjects had a mean AUCo_∞ comparable to that of healthy subjects. Median T_max was shorter in liver impairment subjects when compared to healthy subjects. Oral clearance (CL/F) values were lower in Child-Pugh B and Child-Pugh C subjects as compared with healthy subjects and Child-Pugh A subjects. Mean t½ of MNTX was 16 h for healthy subjects, and was largely similar for subjects with hepatic impairment (Child-Pugh A: 19 h, Child-Pugh B: 15 h, Child-Pugh C: 17 h). In subjects with hepatic impairment, systemic exposure parameters for the MNTX metabolites M4, and M5 were lower than those of healthy subjects. For M2, systemic exposure parameters showed no clear relationship to the extent of hepatic impairment. For C_max, AUCo-24, AUCiast, and AUCo-_∞, the 90% CIs for the ratios of for healthy subjects versus those with hepatic impairment were outside of the range of 80% to 125% for MNTX and the three metabolites.

Administration of a single, 450 mg dose of MNTX (Formulation B) to subjects with varying degrees of hepatic impairment (Child-Pugh A, B, or C) resulted in increased systemic exposure when compared to MNTX administration to healthy subjects. Despite the increased exposure, MNTX was well tolerated in both healthy subjects and hepatic impairment subjects with a low incidence of TEAEs, none of which were considered related to study drug.

Given the less than 2-fold increase in C_max and no increase in AUC in Child-Pugh A subjects compared with healthy subjects, no dosage adjustment is recommended in patients with mild hepatic impairment.

Based on the increases in MNTX C_max and AUC observed in subjects with moderate to severe hepatic impairment in this study, dose adjustments in these populations are recommended. Proposed dose adjustments are based on the following observations and assumptions:

No clinically significant changes in MNTX half-life were observed in subjects with hepatic impairment. Accordingly, no significant effects on MNTX accumulation after multiple dose administration are anticipated in hepatic impairment patients.

Decreased systemic exposure of metabolites M4 and M5 were observed; however, these metabolites do not contribute to the efficacy of MNTX. Accordingly, these PK alterations do not affect the dose adjustment recommendations .

In previous studies (Example XX), systemic exposure increased in a dose proportional fashion across MNTX doses of 150 mg once daily (QD) to 450 mg QD. Therefore, it is assumed that changes in MNTX dose will result in approximately dose -proportional changes in systemic exposure in patients with OIC and hepatic impairment.

The observed MNTX C_max and AUCo-_∞ values after a single dose of 450 mg in healthy subjects and subjects with mild hepatic impairment (Child-Pugh Class A) from this study and predicted C_max and AUCo-_∞ values after a single dose of 150 mg in subjects with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child- Pugh Class C) are displayed in Figure 36. The left panel in each plot (Figure 36) represents the observed values in healthy subjects and subjects with mild hepatic impairment (Child- Pugh Class A) after a single dose of 450 mg MNTX. The right panel in each plot displays the predicted values in subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment after a single dose of 150 mg MNTX. A MNTX dose of 150 mg is anticipated to result in systemic exposures in Child- Pugh B and C subjects similar to those observed in healthy subjects that are administered a MNTX dose of 450 mg. Given that no clinically significant effects on MNTX half-life were observed in hepatic impairment subjects, no adjustment in dose frequency is warranted. Therefore, a dose of 150 mg QD is recommended for subjects suffering from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C).

Embodiments are directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from hepatic impairment. In some embodiments, the subject suffers from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C). In some embodiments, the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from hepatic impairment. For example, the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.

EXAMPLE 12: EFFECT OF RENAL IMPAIRMENT UPON DOSING

Multiple studies have demonstrated that MNTX is excreted unchanged in the urine. A study was conducted to assess the pharmacokinetics of MNTX after subcutaneous (SC) administration in healthy subjects and subjects with varying degrees of renal impairment. The results indicated that renal function impairment had a marked effect on the pharmacokinetics of MNTX, consistent with its renal excretion. The extent of the effect on MNTX pharmacokinetics was qualitatively consistent with the degree of renal function impairment. However, an 8- to 9-fold reduction in renal clearance (normal renal function - CIR = 441 + 149 mL/min, severe renal impairment - C1R = 52 + 28 mL/min) resulted in an approximate 2-fold increase in total MNTX exposure (normal renal function - AUC_∞ = 433 + 92 ng.h/mL, severe renal impairment - AUC_∞= 822 + 76 ng.h/mL). Mean C_max in subjects with severe renal impairment (304 ng/mL) was approximately 1.2-fold greater than the mean value in subjects with normal renal function (257 ng/mL). The less-than-proportional effect of renal impairment on increases in systemic exposure may be related to the division of excretion between renal and metabolic clearance pathways. Based on the increases in MNTX C_max and AUC observed in subjects with severe renal impairment in the study, dose adjustment in that population is recommended. For oral administration of MNTX, a proposed dose adjustment is based on the following observations and assumptions: (i) C_max rather than AUC is associated with the clinical efficacy of MNTX, (ii) mean AUCo-_∞ and C_max values increased 1.9- and 1.2-fold, respectively, in subjects with severe renal impairment compared to subjects with normal renal function after MNTX 0.3 mg/kg SC; similar increases in AUCo-_∞ and C_max values are anticipated after oral administration of MNTX in severe renal impairment, (iii) systemic exposure increased in a dose proportional fashion across MNTX doses of 150 mg once daily (QD) to 450 mg QD in previous studies; it is assumed that changes in MNTX dose will result in approximately dose- proportional changes in systemic exposure in patients with OIC and renal impairment. Data from a comparison study (Example 9) and a pharmacokinetic/pharmacodynamics model (Example 13) were used to predict the range of C_max and AUCo-_∞ values after administration of a 450 mg or 300 mg oral dose of MNTX in OIC patients with severe renal impairment given the assumptions discussed above. The predicted C_max values were compared to the observed values after administration of 450 mg in the comparison study (Example 9). Plots of the observed and predicted PK parameters are displayed in Figure 37. The left panel of Figure 37 illustrates observed MNTX C_max values after administration of 450 mg in the comparison study (Example 9) and predicted C_max values after administration of 450 mg or 300 mg in subjects with severe renal impairment. The right panel of Figure 37 illustrates observed MNTX AUCo-_∞ values after administration of 450 mg PO in the comparison study (Example 9) and predicted AUCo-_∞ values after administration of 450 mg or 300 mg in subjects with severe renal impairment. Open circles in Figure 37 represent individual observed or predicted values, and lines represent median observed or predicted values.

Oral administration of 300 mg MNTX in subjects with severe renal impairment is predicted to result in an approximate decrease of 20% in median C_max and an approximate 27% increase in median AUCo-_∞ relative to the observed values after administration of 450 mg in OIC patients in the comparison study (Example 9). Based on C_max comparisons, an oral dose of 300 mg MNTX in patients with OIC and severe renal impairment is expected to provide efficacy comparable to that observed after administration of 450 mg in subjects with normal renal function and have an acceptable safety profile. Therefore, a dosing regimen of 300 mg once daily is recommended in patients with severe renal impairment. Embodiments are directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from renal impairment. In some embodiments, the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from renal impairment. For example, the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day. In some embodiments, the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.

EXAMPLE 13: DEVELOPMENT OF A

PHARMACOKINETIC/PHARMACODYNAMIC MODEL

Concentration-response relationships generally are continuous such that the relationships determined from one dosage form or route of administration can be applied to the relationships for another dosage form even when plasma concentrations are different after administration of those dosage forms. Accordingly, data across multiple studies demonstrating dose -response and systemic exposure-response (ie, pharmacokinetic/pharmacodynamics, or PK/PD) relationships for MNTX were analyzed to, extrapolate efficacy results from the studies for administration of a subcutaneous (SC) formulation of methylnaltrexone to administration of an oral formulation of methylnaltrexone. The objectives of these analyses were to develop a PK/PD model of the relationship between plasma concentrations of MNTX and clinical endpoints measured in subcutaneous administration clinical trials and to examine the effect of the covariates of C_max and T_max of MNTX, age, sex, weight, and route of administration on the clinical endpoints.

The efficacy endpoints included in this analysis were the occurrence of a bowel movement (laxation) within 4 hours after administration and the time to laxation after administration of the first dose of study drug. Blood samples for analysis of plasma MNTX concentrations were collected over different intervals across studies. Therefore, MNTX maximum observed plasma concentration (C_max) was used to develop the PK/PD models.

Data from six studies were pooled for the analysis. A graphical analysis was conducted to explore the relationship between MNTX C_max and the proportion of subjects that experienced laxation within 4 hours after administration across the studies. Quintiles of the observed C_max values after administration of MNTX were determined and the proportion of subjects within each C_max quintile who experienced laxation within 4 hours after administration of MNTX was determined. Each C_max quintile range included 77 or 78 observations. Results from a total of 124 subjects were included in the calculation of the proportion of subjects who experienced laxation within 4 hours after administration of placebo. A plot of the proportion of subjects who experienced laxation within 4 hours after administration versus the C_max quintile midpoint is displayed in Figure 38.

From the graphical analysis of the data, a concentration-dependent effect on the proportion of subjects who experienced laxation within 4 hours after administration was evident. The proportion of subjects who experienced laxation within 4 hours after administration increased consistently over the range of observed C_max values. The proportion of subjects that experienced laxation within 4 hours after administration approached 1 at the greatest observed plasma MNTX C_max values.

The time to laxation versus plasma MNTX C_max is displayed in Figure 39. Greater plasma MNTX C_max values generally were associated with shorter times to laxation. While individual data show PK and PD variability (not unexpected given that the data were collected under varying conditions in 6 separate studies), the data nonetheless show a clear, continuous relationship between higher plasma MNTX C_max and shorter time to laxation.

Seventy percent of the original data set was randomly selected to create a model development data set. The model development data set was used to develop PK/PD models for two clinical endpoints (laxation within 4 hours after administration and time to laxation) and to test the effects of significant covariates (age, weight, sex, C_max, T_max and route of administration) on the clinical endpoints. The remaining 30% of the data were used as a model validation data set. The predictive performance of the models was investigated by comparing the clinical endpoints predicted with the final model parameters and the covariates from the validation data set to the observed clinical endpoints in the validation data set.

A logistic regression model was used to describe the relationship between the probability of laxation within 4 hours after MNTX administration and the selected covariates, including C_max. The data for laxation response within 4 h after dose administration was characterized as a binomial response and modeled using the following equation (1):

(1) where a is an intercept parameter, β; is the model coefficient for the i covariate, and Covi is the 1^th covariate value.

A time to event (TTE) analysis was also conducted to describe the relationship between the time to laxation after MNTX administration and the selected covariates. A Weibull function was used to describe the underlying hazard (i.e., the occurrence of laxation) rate over the 24 hour observation period. The Weibull function was described by the parameters v and λ [dweib(v, λ)] where v is a constant and λ is a function of methylnaltrexone C_max. The effect of methylnaltrexone C_max on λ was described using the following equation (2):

(2) where β₀ is and intercept parameter and β; and Covi are the coefficient and value of the i^th covariate, respectively, tested in the model. The Weibull function was fit to the time to laxation data in the model development data set. The parameters determined from the best fit of the model to the model development data were used to predict the survival rate of subjects in the validation data set with the following functions: The hazard rate (HR_pre(j) and survival rate (SR_pred) at selected covariate values were estimated with the best-fit model parameters with the following equations (3) and (4):

(3)

SRpred = e -^HRvrea

(4) where HR_pred, is the predicted hazard rate, SR_pred is the predicted survival rate, t is the time at which the fraction surviving is estimated, and β_ί, Covi, and v are as defined previously.

The TTE model identified a concentration-dependent effect on the time to laxation with T_max as an additional significant covariate. The model generally described the observed fraction of subjects that had experienced laxation over the 24 hour period after administration in subjects in the validation data set. The logistic regression model demonstrated that MNTX Cmax and T_max were the significant predictors of the probability of laxation within 4 hours after administration. The effects of MNTX C_max and T_max on the probability of laxation within 4 hours after administration were independent of the route of administration (oral versus SC or intravenous). The final model parameters and covariates from the validation data set adequately predicted the observed proportion of subjects who achieved laxation within 4 hours after administration in the validation data set. The model-predicted probabilities of laxation within 4 hours versus MNTX C_max for four T_max values are displayed in Figure 40. The observed proportion of subjects who achieved laxation within 4 hours after administration versus the mean C_max for each T_max category from the validation data set are displayed on each graph. The solid line in each plot (Figure 40) represents the median predicted probability of laxation within 4 hours versus natural log of MNTX C_max + 1. The shaded area in each plot (Figure 40) represents the 95% credible interval for predicted probability of laxation within 4 hours versus natural log of MNTX C_max + 1. The closed circles in each plot (Figure40) represents the observed proportion of subjects that experienced laxation within 4 hours after administration versus mean ln(C_max) + 1 in each T_max group in the validation data set.

Concentration-dependent relationships were identified for MNTX and two clinical endpoints of the relief of opioid induced constipation: (i) the probability of laxation within 4 hours after administration and (ii) the time to laxation. Both endpoints include a time component and both the logistic regression and TTE models identified an expected effect of Tmax on the clinical endpoints. The results from the logistic regression model demonstrated that MNTX C_max and T_max are accurate predictors of clinical effect.

Although the MNTX pharmacokinetics profile is different after oral or parenteral administration, neither model identified oral administration as a significant covariate. These results indicate that the PK/PD relationship for MNTX is independent of the route of MNTX administration. The findings that route was not a significant covariate in either PK/PD model is consistent with the hypothesis that clinical effects are determined primarily by systemic exposure to the parent compound MNTX. Modeling results that demonstrated that methyl- 6a-naltrexol and methyl-6P-naltrexol were not significant covariates in the logistic regression model confirm that the parent compound is primarily responsible for the clinical effects observed after administration of MNTX. The logistic regression model accurately predicted the proportion of subjects that achieved laxation within 4 hours after administration in the validation data set, demonstrating that the concentration-effect relationship was well-described. Although a concentration- dependent effect was detected during development of the TTE model, validation results indicate that C_max, and T_max alone cannot predict the time to laxation with accuracy. Both PK/PD models demonstrated that laxation is likely to occur more rapidly when C_max is large and T_max values are short (i.e. C_max occurs rapidly).

The predictive performance of the final logistic regression model was adequate to demonstrate that the concentration-effect relationship was well defined by the model. The results also demonstrate that the relationship between plasma MNTX concentrations and the clinical effect is continuous over a large range of concentrations. The model demonstrated that a meaningful clinical effect of laxation would be predicted by the plasma MNTX concentrations observed at a dosing regimen of MNTX 450 mg orally once daily.

Embodiments are directed to predicting a clinical response to administration of methylnaltrexone, wherein the methods include administering a composition comprising methylnaltrexone to a subject and analyzing the subject's plasma MNTX concentration, wherein a measurement of C_max > 100 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C_max > 125 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C_max > 150 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C_max > 175 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C_max > 200 ng/mL indicates that the subject is a responder. In some embodiments, the clinical response is a laxation response within about four hours of administration of methylnaltrexone. In some embodiments, prediction of the clinical response indicates a response regardless of the route of administration of methylnaltrexone. For example, in some embodiments, a clinical response based on measurement of C_max after subcutaneous administration of methylnaltrexone is an indication that clinical response will occur in the subject after administration of methylnaltrexone by a non-subcutaneous route.

Embodiments are also directed to determining a suitable dosage amount for a given condition, wherein the methods include obtaining a group of subjects with the given condition, administering methylnaltrexone to the subjects, analyzing the group of subjects for plasma MNTX concentration, and comparing the median or mean plasma MNTX concentration for the group with the median or mean plasma MNTX concentration of a group of healthy subjects, wherein comparison of the Cmax values for each group is indicative of a suitable dosage amount for the group of subjects with the given condition. In some embodiments, determination of the suitable dosage amount is provided for oral administration of methylnaltrexone.

EXAMPLE 14: METHYLNALTREXONE EXHIBITS A CLEAN DRUG-DRUG INTERACTION PROFILE

Methylnaltrexone does not have any known clinically significant drug interactions, therefore offering an important safety benefit, as illustrated by the studies described below.

The permeability of [15,16- H] MNTX across Caco-2 monolayers and status as a substrate for P-gp was evaluated in Study RPT-66293. In Caco-2 cells, MNTX (1, 5, and 25 μΜ) had low permeability with transport rates of < 20 nm/sec. The ratio of the transport rates (B→A:A→B) for MNTX were 0.922, 1.05 and 1.85 at 1, 5, and 25 μΜ, respectively. In the presence of the P-gp inhibitor verapamil (100 μΜ), the ratios of B→A:A→B transport rates for MNTX were 1.04, 1.05, and 1.31 at 1, 5, and 25 μΜ, respectively. The low transport ratios for MNTX (< 2) and lack of substantive effect of verapamil on permeability suggest that MNTX is not a substrate for P-gp. The low permeability of MNTX across Caco-2 monolayers is consistent with its low oral bioavailability in clinical studies, and the negative result for P-gp substrate status indicates that MNTX absorption is unlikely to be increased due to drug-drug interactions.

In studies conducted to characterize the in vitro inhibitory potency of MNTX for major CYP450 enzymes (CYPs 1A2, 2A6, 2B6, 2D6, 2C9, 2C19, 2E1, and 3A4) in human liver microsomes, no significant inhibition was observed up to the highest concentrations tested with the exception of CYP2D6, with a 50% inhibitory concentration (IC₅₀) of 15.92 μΜ and K_; of 7.93 μΜ (107N-0304 [RPT63619], RPT71772). In a follow-up study 7434-111 (RPT63620) to further investigate the inhibitory effects of MNTX on CYP2D6, moderate competitive inhibition of CYP2D6 was observed in vitro; the apparent Kj was 11 to 18 μΜ.

No MNTX-induced induction of CYP enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19 or CYP3A4 was observed in human hepatocytes (RPT65259).

Because the CYP isoform CYP2E1 was not part of the initial evaluation, a separate study was conducted to evaluate the potential of MNTX to induce the catalytic activity of CYP2E1 in freshly prepared human hepatocytes following in vitro exposure to 1, 5, or 25 μΜ MNTX (RPT72520). None of the 5 human hepatocyte cultures exhibited induction of CYP2E1 activity at 1 μΜ MNTX. Hepatocyte cultures from one donor showed limited CYP2E1 induction (119% of vehicle control) at 5 μΜ MNTX and mild induction (133% of vehicle control) at 25 μΜ MNTX. A second donor culture also exhibited CYP2E1 induction (139% of vehicle control) at the 25 μΜ MNTX concentration. Variation in the occurrence of CYP2E1 induction was seen among hepatocyte cultures from different donors. CYP2E1 induction, when it did occur, was only observed with concentrations in excess of the anticipated clinical exposure levels. Therefore, clinically significant MNTX drug-drug interactions based on induction of CYP2E1 activity are unlikely.

Studies also were conducted to investigate the in vitro inhibitory potency of MNTX sulfate, methyl-6a-naltrexol, and methyl-6P-naltrexol for major CYP450 isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5) in human liver microsomes (XT25033). Results of the study demonstrated that MNTX sulfate, methyl-6a- naltrexol, and methyl- 6 β-naltrexol did not cause direct, time-dependent or metabolism- dependent inhibition of any of the CYP isozymes investigated at concentrations up to 4500, 1000, or 500 ng/mL, respectively. Furthermore, the metabolites did not induce CYP1A2, CYP2B6, or CYP3A4 activity in vitro at concentrations up to 60 μΜ (26.2 μg/mL, 21.5 μg/mL, and 21.5 μg/mL for MNTX sulfate, methyl-6a-naltrexol, and methyl-6P-naltrexol, respectively), with the exceptions of 4 points (XT23038). At none of the points was the induction greater than 2.8-fold the baseline activity and induction at all points was less than 12% the effect of the respective positive control inducer. The highest concentrations of each metabolite in which no inhibition of CYP450 activity was observed in vitro was approximately 100-fold greater than the mean C_max values observed after oral administration of 450 mg MNTX. These results demonstrate that interactions with concomitant medications that are substrates for these CYP450 isozymes are not likely to occur.

Methylnaltrexone and metabolites were investigated as substrates and inhibitors of the transporters P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, and MATE2-K. Methylnaltrexone was not a substrate for any of the transporters examined, with the exception of OCT2, MATE1, and MATE2-K. Cimetidine is a known inhibitor of OCT1- and OCT2-mediated drug uptake. Concomitant administration of 400mg cimetidine daily and 24 mg MNTX SC resulted in a reduction in MNTX renal clearance but resulted in no clinical meaningful change in mean C_max and AUCo-_∞ relative to administration of MNTX alone. These results indicate that inhibition of OCTl and OCT2 had no clinically meaningful effects on systemic disposition of MNTX.

Methyl-6a-naltrexol and methyl-6P-naltrexol were not substrates for any of the transporters tested with the exception of OCTl, OCT2, MATE1, and MATE2-K. Methylnaltrexone sulfate was a substrate for BCRP and MATE2-K only.

Methylnaltrexone did not inhibit any of the transporters at the concentrations tested (10 - 1800 μΜ). Inhibition of the transporters by the MNTX metabolites at concentrations of up to 10 μΜ (3.59 μg/mL for methyl-6a-naltrexol and methyl-6P-naltrexol and 4.37 μg/mL for MNTX sulfate) also was investigated. No significant inhibition (<50%) was observed for any of the transporters by any of the metabolites. The MNTX C_max:IC₅o ratio was < 0.0114 for all transporters. The C_max:IC₅o ratios for the MNTX metabolites all were < 0.041. These results indicate that the risk of a clinically significant interaction due to induction or inhibition of drug metabolizing enzymes or drug transporters is minimal. Table 17 summarizes the results and interpretation of in vitro drug interaction studies for transporter- based interactions.

Table 17. In vitro study result summary and interpretation of transporter-based interactions for MNTX and metabolites for various studies

Test compound Transporter IC50 (μΜ) ffl ICso Ratio [I2] IC5o Ratio Unbound C_max IC₅o Ratio Likely Interaction (Y/N)

MNTX P-gp NI at 500 μΜ < 0.001 0.010 N

BCRP NI at 500 μΜ < 0.001 0.010 N

MRP2 NI at 100 μΜ N

OATP1B1 >1800 < 0.001 N

OATP1B3 >1800 < 0.001 N

OCT1 >25 0.005 N

OCT2 >100 0.001 N

OCT2 >10 0.001 N

OAT1 >10 0.001 N

OAT3 >10 0.001 N

MATE1 >10 0.001 N

MATE2-K >10 0.001 N

MNTX sulfate P-gp >10 < 0.005 N

BCRP >10 < 0.005 N

MRP2 >10 N

OATP1B1 >10 < 0.005 N

OATP1B3 >10 < 0.005 N

OCT1 >10 0.004 N

OCT2 >10 0.004 N

OAT1 >10 0.004 N

OAT3 >10 0.004 N

MATE1 >10 0.004 N

MATE2-K >10 0.004 N

Methyl-6a-naltrexol P-gp >10 < 0.003 N

BCRP >10 < 0.003 N

MRP2 >10 N

OATP1B1 >10 < 0.003 N

Test compound Transporter ICso (μΜ) ffl ICso Ratio [UyiCso Ratio Unbound C_max IC5o Ratio Likely Interaction (Y/N)

OATP1B3 >10 < 0.003 N

OCT1 >10 0.002 N

OCT2 >10 0.002 N

OAT1 >10 0.002 N

OAT3 >10 0.002 N

MATE1 >10 0.002 N

MATE2-K >10 0.002 N

Methyl-6P-naltrexol P-gp >10 < 0.001 N

BCRP >10 < 0.001 N

MRP2 >10 N

OATP1B1 >10 < 0.001 N

OATP1B3 >10 < 0.001 N

OCT1 >10 0.001 N

OCT2 >10 0.001 N

OAT1 >10 0.001 N

OAT3 >10 0.001 N

MATE1 >10 0.001 N

MATE2-K >10 0.001 N

Abbreviations: [I] = maximum plasma concentration of putative inhibitor; [12] = estimated maximal intestinal concentration of putative inhibitor; NI = no inhibition

Note: Calculations and interaction potential are based on the FDA draft Guidance for Industry: Drug Interaction Studies— Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (2012)

Results of in vitro and ex vivo studies indicated that MNTX was a substrate of the human OCT1 transporter (RPT66294; RPT66295) and that MNTX urinary clearance exceeded the glomerular filtration rate by approximately 7-fold in a perfused rat kidney model (RPT 67270), consistent with pharmacokinetic findings in humans indicating that MNTX is actively secreted into urine following IV dosing (study MNTX 102 [RPT65255]). Methylnaltrexone was found to be a substrate of the hOCTl transporter but not of the hOATl transporter in frog oocytes transfected with the corresponding human transporters (RPT66294; RPT66295). OCTl-mediated MNTX transport was only slightly inhibited by therapeutic concentrations of several common basic drugs.

A clinical study conducted with a 20 mg intravenous dose of MNTX followed by 400 mg cimetidine orally every 8 hours indicated that co-administration of cimetidine (a potent inhibitor of the hOCTl drug transporter) did not cause any clinically meaningful changes in plasma C_max and total exposure to MNTX (MNTX1304).

Based on the results of the in vitro studies 107N-0304 (RPT63619) and 7434-111 (RPT63620), a subsequent clinical drug-drug interaction study (MNTX1108) with IV and SC MNTX was conducted to evaluate the potential for MNTX to inhibit CYP2D6 to a clinically significant extent; results showed no significant effect of MNTX on the metabolism of CYP2D6 substrate dextromethorphan. Because the expressions of CYP2D6 in the intestine and liver are minimal, 0.7% and 2% of all cytochromes P450, respectively (33), the potential for a drug-drug interaction effect following oral MNTX dosing is expected to be insignificant, consistent with what has been observed following parenteral MNTX administration. In addition, an MNTX-cimetidine drug-drug interaction study (described in the previous section) in human subjects indicated that there was no clinically relevant interaction.

Overall, in vitro testing of MNTX and its metabolites has shown little or no interaction with CYP enzymes or drug transporters. Based on these data, systemic pharmacokinetic data, and predicted intestinal concentrations, oral MNTX administration at a single daily dose of 450 mg is not anticipated to result in any clinically significant drug-drug interactions.

The absence of predicted clinically significant drug-drug interactions for MNTX after oral or SC administration may provide a safety advantage versus the currently marketed orally administered peripheral opioid antagonist naloxegol. Naloxegol, as a CYP3A4 and P- gp substrate, has labeling that warns against co-administration with moderate to strong CYP3A4 inhibitors and strong CYP3A4 inducers because of the risk of significant effects on naloxegol plasma concentrations. These restrictions would not be required for MNTX.

EXAMPLE 15

1 INDICATIONS AND USAGE

1.1 Opioid- Induced Constipation in Adult Patients with Chronic Non-Cancer Pain

RELISTOR® tablets and subcutaneous injection are indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

1.2 Opioid-induced Constipation in Adult Patients with Advanced Illness

RELISTOR® subcutaneous injection is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Information

• Be within close proximity to toilet facilities once RELISTOR® is administered.

• Discontinue RELISTOR® administration if treatment with the opioid pain

medication is also discontinued.

• Re-evaluate the continued need for RELISTOR® when the opioid regimen is changed to avoid adverse reactions.

• In patients with chronic non-cancer pain and opioid-induced constipation:

o RELISTOR® has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. Sustained exposure to opioids prior to starting RELISTOR® may increase the patient' s sensitivity to the effects of RELISTOR [see Clinical Studies (14.1)].

o Discontinue all maintenance laxative therapy prior to initiation of

RELISTOR®. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR® after three days. Tablets

In patients with chronic non-cancer pain and opioid-induced constipation, take RELISTOR® tablets with water on an empty stomach at least 30 minutes before the first meal of the day.

Subcutaneous Injection

RELISTOR® is for subcutaneous use only.

Inject RELISTOR® subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

2.2 Opioid-induced Constipation in Adult Patients with Chronic Non-Cancer Pain

The recommended dosage of RELISTOR® tablets is 450 mg (three 150 mg tablets) taken orally once daily in the morning.

The recommended dosage of RELISTOR® subcutaneous injection is 12 mg once daily [see Clinical Studies (14.1 )].

2.3 Opioid-induced Constipation in Adult Patients with Advanced Illness

The recommended dose of RELISTOR® administered subcutaneously is 8 mg for adult patients weighing 38 kg to less than 62 kg and 12 mg for patients weighing 62 kg to 114 kg. Adult patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg. The recommended dosage regimen is one dose every other day, as needed, but no more frequently than one dose in a 24-hour period, [see Clinical Studies (14.2)].

See Table 18 to determine the correct dose by patient weight and injection volume to be administered. The pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients requiring dosing calculated on a mg/kg basis should not be prescribed pre-filled syringes.

Table 18. Weight-based dosing of RELISTOR® and corresponding injection volume for adult patients with opioid-induced constipation and advanced illness Weight of Adult Patient Subcutaneous

Injection Volume Dose

Less than 38 kg 0.15 mg/kg See below*

38 kg to less than 62 kg 8 mg 0.4 niL

62 kg to 114 kg 12 mg 0.6 niL

More than 114 kg 0.15 mg/kg See below*

*The injection volume for these patients should be calculated using the following method: Multiply the patient weight in kilograms by 0.0075 and round up the volume to the nearest

0.1 mL.

2.4 Use in Patients with Severe Renal Impairment Tablets

In adult patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault), a RELISTOR® dose of 2 tablets once daily (300 mg/day) is recommended [see Use in Specific Populations (8.6)]. No dosage adjustment is recommended for adult patients with mild to moderate renal impairment.

Subcutaneous Injection

In adult patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault), dose reduction of RELISTOR® by one-half is recommended [see Use in Specific Populations (8.6)]. No dosage adjustment is recommended for adult patients with mild to moderate renal impairment.

The pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients with severe renal impairment should be prescribed single-use vials to ensure correct dosing.

2.5 Use in Patients with Hepatic Impairment Tablets

In adult patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), a RELISTOR® dose of 1 tablet once daily (150 mg per day) is recommended [see Use in Specific Populations (8.7)]. No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh Class A). Subcutaneous Injection

No dose adjustment is required for patients with mild or moderate hepatic impairment.

2.6 ADMINISTRATION AND STORAGE Tablets

RELISTOR® tablets should be taken orally with water on an empty stomach at least 30 minutes before the first meal of the day [see Clinical Pharmacology (12.3)].

Subcutaneous Injection

RELISTOR® is a sterile, clear, and colorless to pale yellow aqueous solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vial if any of these are present.

Single-use Vials

Once drawn into the 1 mL syringe with a 27-gauge x ½-inch needle, if immediate administration is not possible, store at ambient room temperature and administer within 24 hours. Discard any unused portion that remains in the vial. Advise patients concerning proper training in subcutaneous technique.

Single-use Pre-filled Syringes

Adult patients requiring an 8 mg or 12 mg dose should be prescribed pre-filled syringes. Do not remove the pre-filled syringe from the tray until ready to administer.

3 DOSAGE FORMS AND STRENGTHS

Tablet:

• 150 mg tablet supplied as white, round, biconvex, film coated tablets, debossed with "REL" on one side and plain on the other side.

Single-use Vial:

• 12 mg/0.6 mL solution for subcutaneous injection, for use with a 27 gauge x ½- inch needle and 1 mL syringe • 12 mg/0.6 mL solution for subcutaneous injection, with one 1 mL syringe with retractable 27 gauge x ½-inch needle, two alcohol swabs

Single-use Pre-filled Syringe:

• 8 mg/0.4 mL solution for subcutaneous injection, with a 29-gauge x ½-inch fixed needle and a needle guard

• 12 mg/0.6 mL solution for subcutaneous injection, with a 29-gauge x ½-inch fixed needle and a needle guard

4 CONTRAINDICATIONS

RELISTOR® is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported in adult patients with opioid- induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR® in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR® in patients who develop this symptom [see Contraindications (4)1.

5.2 Severe or Persistent Diarrhea

If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR® and consult their healthcare provider. 5.3 Opioid Withdrawal

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR® [see Adverse Reactions (6.1)]. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR® in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.

6 ADVERSE REACTIONS

Serious and important adverse reactions described elsewhere in labeling include:

• Gastrointestinal perforation [see Warnings and Precautions (5.1)]

• Severe or persistent diarrhea [see Warnings and Precautions (5.2)]

• Opioid withdrawal [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Opioid-induced Constipation in Adult Patients with Chronic Non-Cancer Pain

The safety of RELISTOR® tablets was evaluated in a double-blind, placebo- controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12- week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR® tablets 450 mg (200 patients) orally or placebo (201 patients) [see Clinical Studies (14.1)]. After 4 weeks of double-blind once daily treatment, patients continued double-blind treatment on an as needed basis (but no more than one dose per day) for an additional 8 weeks.

Adverse reactions in adult patients with opioid-induced constipation and chronic non- cancer pain receiving RELISTOR® tablets are shown in Table 19.

Table 19. Adverse Reactions* in 12- Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR® Tablets in Adult Patients with Opioid-induced Constipation and Chronic Non-Cancer Pain RELISTOR®

Placebo

450 mg

n = 201

Adverse Reaction n = 200

Abdominal Pain 11% 9%

Diarrhea 8% 4%

Headache 5% 4%

Abdominal Distention 4% 3%

Anxiety 4% 2%

Hyperhidrosis 3% 2%

Blood Creatine Phosphokinase

2% 1%

Increased

Adverse reactions occurring in > 2 % of patients receiving RELISTOR® tablets 450 and at an incidence greater than placebo.

The safety of RELISTOR® subcutaneous injection was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non- cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR® 12 mg once daily (150 patients) or placebo (162 patients) [see Clinical Studies (14.1)]. After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR® 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.

Adverse reactions in adult patients with opioid-induced constipation and chronic non- cancer pain receiving RELISTOR® subcutaneous injection are shown in Table 20. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Table 20. Adverse Reactions* in 4- Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR® Subcutaneous Injection in Adult Patients with Opioid- induced Constipation and Chronic Non-Cancer Pain RELISTOR®

Placebo

12 mg once daily

n = 162

Adverse Reaction n = 150

Abdominal Pain 21% 6%

Nausea 9% 6%

Diarrhea 6% 4%

Hyperhidrosis 6% 1%

Hot Flush 3% 2%

Tremor 1% < 1%

Chills 1% 0%

* Adverse reactions occurring in > 1 % of patients receiving R ELISTOR® 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR® 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR® dosing. Use of RELISTOR® 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain [see Dosage and Administration (2.2)]. The rates of discontinuation due to adverse reactions during the double-blind period (Study 2) were higher in the RELISTOR® once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR® once daily group (2%).

The safety of RELISTOR® subcutaneous injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR® 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4- week double-blind period of Study 2. Additionally, in Study 3, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR®. Opioid- Induced Constipation in Adult Patients with Advanced Illness

The safety of RELISTOR® subcutaneous injection was evaluated in two, double- blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 4 included a single-dose, double-blind, placebo-controlled period, whereas Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period [see Clinical Studies (14.2)].

The most common (> 5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR® are shown in Table 21 below.

Table 21. Adverse Reactions from all Doses in Double-Blind, Placebo-Controlled Clinical Studies of RELISTOR® Subcutaneous Injection in Adult Patients with Opioid-induced

Constipation and Advanced Illness*

(0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR® (1%) and placebo (2%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of RELISTOR® subcutaneous injection. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal

Perforation, cramping, vomiting General Disorders and Administrative Site Disorders

Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported [see Warnings and Precautions (5.3)].

7 DRUG INTERACTIONS

7.1 Other Opioid Antagonists

Avoid concomitant use of RELISTOR® with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

7.2 Drugs Metabolized by Cytochrome P450 Isozymes

In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies with RELISTOR® in pregnant women. The use of RELISTOR® during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

Reproduction studies have been performed with methylnaltrexone administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the MRHD of 0.2 mg/kg/day based on body surface area) and did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses of methylnaltrexone up to 16 mg/kg/day (about 26 times the MRHD of 0.2 mg/kg/day based on body surface area) did not show any embryofetal toxicity. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses of methylnaltrexone up to 100 mg/kg/day (about 81 times the MRHD of 0.2 mg/kg/day based on body surface area).

8.2 Lactation

Risk Summary

It is not known whether RELISTOR® is present in human milk. However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of RELISTOR® have not been established in pediatric patients.

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs [see Nonclinical Toxicology (13.2)].

8.5 Geriatric Use

In the double-blind studies of RELISTOR® administered orally, a total of 136 (10%) patients aged 65 years or older (96 methylnaltrexone, 40 placebo) were enrolled. In the double-blind studies of RELISTOR® administered subcutaneously, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.

8.6 Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment taking tablets or subcutaneous injection.

Tablets

A dose of 2 tablets once daily (300 mg per day) is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault) [see Dosage and Administration (2.4)]

Subcutaneous Injection

Dose-reduction by one half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault) [see Dosage and Administration (2.4)].

8.7 Hepatic Impairment Tablets

A dose of 1 tablet once daily (150 mg per day) is recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5)].

Subcutaneous Injection

No dose adjustment is required for patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

During clinical trials of RELISTOR® administered orally and subcutaneously, cases of methylnaltrexone bromide overdose were reported. A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate.

If a patient on opioid therapy receives an overdose of RELISTOR®, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

11 DESCRIPTION

RELISTOR® (methylnaltrexone bromide) is a mu-opioid receptor antagonist. The chemical name for methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C₂iH₂₆N0₄Br, and the molecular weight is 436.36.

The structural formula is:

RELISTOR® tablets for oral administration are film-coated and contain 150 mg of methylnaltrexone bromide. Inactive ingredients are silicified microcrystalline cellulose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, crospovidone, poloxamer 407, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

RELISTOR® subcutaneous injection is a sterile, clear and colorless to pale yellow aqueous solution. Each 3 mL vial contains 12 mg of methylnaltrexone bromide in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Each 8 mg/0.4 mL pre-filled syringe (1 mL syringe) contains 8 mg of methylnaltrexone bromide in 0.4 mL of water. The excipients are 2.6 mg sodium chloride USP, 0.16 mg edetate calcium disodium USP, and 0.12 mg glycine hydrochloride. Each 12 mg/0.6 mL pre-filled syringe (1 mL syringe) contains 12 mg of methylnaltrexone bromide in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally- acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a randomized, double-blind placebo- and (open-label) moxifloxacin-controlled 4-period crossover study, 56 healthy subjects were administered methylnaltrexone bromide 0.3 mg/kg and methylnaltrexone bromide 0.64 mg/kg by intravenous infusion over 20 minutes, placebo, and a single oral dose of moxifloxacin. At a dose approximately 4.3 times the maximum recommended dose (7.5 times the mean peak plasma concentration for subcutaneous injection and 15 times the peak plasma concentration for tablets), methylnaltrexone does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption Tablets

Following administration of a single 450-mg oral dose in OIC patients or healthy subjects, methylnaltrexone achieved peak concentrations (C_max) at approximately 1.5 hours. Based on the half-life of methylnaltrexone in OIC patients (6.6 h), no accumulation is expected after once-daily administration. Table 22. Pharmacokinetic Parameters of Methylnaltrexone Following Oral Doses

i) Expressed as mean (SD).

ii) Expressed as median (range).

Food Effect in Healthy Subjects

Administration of a single 450 mg oral dose of methylnaltrexone to healthy subjects under fed conditions resulted in a decrease in systemic exposure when compared to methylnaltrexone administration under fasted conditions. AUCo-∞ and C_max decreased by approximately 47% and 64%, respectively, after administration with a high-fat meal relative to administration in the fasted state. Median T_max was delayed in the fed state when compared with the fasted state (4.0 hours versus 2.0 hours, respectively). This decrease in exposure can be clinically significant; therefore, RELISTOR® should be taken only on an empty stomach (30 minutes before the first meal of the day).

Subcutaneous Injection

Following subcutaneous administration, methylnaltrexone achieved peak concentrations (C_max) at approximately 0.5 hours. Across the range of doses from 0.15 mg/kg to 0.50 mg/kg, mean C_max and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner. There was no accumulation of methylnaltrexone following once-daily subcutaneous dosing of methylnaltrexone bromide 12 mg for seven consecutive days in healthy subjects.

Table 23. Pharmacokinetic Parameters of Methylnaltrexone Following Subcutaneous Doses

Expressed as mean (SD).

'Expressed as median (range). Distribution

The steady-state volume of distribution (Vss) of methylnaltrexone is approximately 1.1 L/kg. The fraction of methylnaltrexone bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis.

Elimination

Following oral administration of a single 450-mg dose in OIC patients, the mean t_1/2 was approximately 6.6 hours.

Following intravenous administration of 0.3 mg/kg, the total clearance of methylnaltrexone is approximately 10.5 + 1.5 mL/min/kg, with renal clearance of 6.37 + 3.0 mL/min/kg. The terminal half-life (t^) is approximately 8 hours.

Metabolism

In a mass balance study, approximately 44% of the administered radioactivity was recovered in the urine over 24 hours with 5 distinct metabolites and none of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6- naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total) appear to be the primary pathways of metabolism. N-demethylation of methylnaltrexone to produce naltrexone is not significant.

After 12 mg subcutaneous once daily dosing the mean AUCo-24 ratio of metabolites to methylnaltrexone at steady-state was 30%, 19%, and 9% for methylnaltrexone sulfate, methyl-6cc-naltrexol, and methyl-6 -naltrexol, respectively. After 450 mg oral once daily dosing, the mean AUCo-24 ratio of metabolites to methylnaltrexone at steady-state was 79%, 38%, and 21% for methylnaltrexone sulfate, methyl-6cc-naltrexol, and methyl-6 -naltrexol, respectively. Methyl-6cc-naltrexol, and methyl-6 -naltrexol are active mu-opioid receptor antagonists and methylnaltrexone sulfate is a weak mu-opioid receptor antagonist; however, metabolites do not appear to contribute to clinical activity.

Methylnaltrexone is conjugated by sulfotransf erase SULT1E1 and SULT2A1 isoforms to methylnaltrexone sulfate. Conversion to methyl-6-naltrexol isomers is mediated by aldo-keto reductase 1C enzymes.

Excretion

After intravenous administration, approximately half of the dose was excreted in the urine (53.6%) and 17.3% of administered dose was excreted in the feces up to 168 hours postdose. Methylnaltrexone is excreted primarily as the unchanged drug in the urine and feces. Active renal secretion of methylnaltrexone is suggested by renal clearance of methylnaltrexone that is approximately 4-5 fold higher than creatinine clearance.

Specific Populations

Age: Geriatric Population

A study was conducted to characterize the pharmacokinetics of methylnaltrexone after a single dose of 24 mg methylnaltrexone via intravenous infusion over 20 min in healthy adults between 18 and 45 years of age and in healthy adults aged 65 years and older. In elderly subjects (mean age 72 years old), mean clearance was about 20% lower (56 L/h versus 70 L/h) and AUC_∞ was 26% higher than in subjects between 18 and 45 years of age (mean age 30 years old).

Renal impairment

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide subcutaneous injection, renal impairment had a marked effect on the renal excretion of methylnaltrexone. Severe renal impairment decreased the renal clearance of methylnaltrexone by 8- to 9-fold and resulted in a 2-fold increase in total methylnaltrexone exposure (AUC). Mean C_max was not significantly changed. No studies were performed in patients with end- stage renal impairment requiring dialysis.

Hepatic impairment

Oral administration of methylnaltrexone in subjects with hepatic impairment (Child- Pugh A, B, or C) resulted in higher systemic exposure when compared to healthy subjects. The mean C_max in subjects with Child-Pugh A hepatic impairment was approximately 1.8- fold higher than that of healthy subjects; in Child-Pugh B and C subjects, C_max was approximately 4.8- and 3.7-fold higher, respectively. Systemic exposure, as measured by AUCo-oo, was comparable between healthy subjects and Child-Pugh A subjects (437 ng.h/mL versus 393 ng.h/mL, respectively), and was 2.5- and 2-fold higher, respectively, in Child- Pugh B and C subjects as compared to healthy subjects.

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone administered subcutaneously has been studied in patients with Child-Pugh Class A (n=8) and B (n=8), compared to healthy subjects. Results showed no meaningful effect of hepatic impairment on the AUC or C_max of methylnaltrexone administered subcutaneously. The effect of severe hepatic impairment on the pharmacokinetics of subcutaneous methylnaltrexone has not been studied.

Drug Interactions

In vitro, methylnaltrexone did not significantly inhibit or induce the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.

In vitro, methylnaltrexone did not induce the enzymatic activity of CYP2E1.

In vitro studies suggested that methylnaltrexone was a substrate of Organic Cation Transporter 1 but not a substrate of Organic Anion Transporter 1 or P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance Protein 2, or Organic Anion-Transporting Polypeptide 1B1 or 1B3. Methylnaltrexone did not inhibit uptake of substrates by P- glycoprotein, BCRP, or Organic Cation Transporter 2 to an extent anticipated to be clinically relevant.

In vitro, the methylnaltrexone metabolites, methylnaltrexone sulfate, methyl-6a- naltrexol and methyl-6P-naltrexol did not inhibit CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. The metabolites of methylnaltrexone did not induce activity of CYP1A2, CYP2B6, or CYP3A4.

Cimetidine

A clinical drug interaction study in healthy adult subjects evaluated the effects of cimetidine, a drug that inhibits the active renal secretion of organic cations, on the pharmacokinetics of methylnaltrexone (24 mg administered as an Γ infusion over 20 minutes). A single dose of methylnaltrexone was administered before cimetidine dosing and with the last dose of cimetidine (400 mg every 8 hours for 6 days). Mean C_max and AUC of methylnaltrexone increased by 10% with concomitant cimetidine administration. The renal clearance of methylnaltrexone decreased about 40%.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year oral carcinogenicity studies have been conducted with methylnaltrexone in CD-I mice at doses up to 200 mg/kg/day (about 81 times the maximum recommended human (MRHD) dose of 0.2 mg/kg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the MRHD of 0.2 mg/kg/day based on body surface area) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the MRHD of 0.2 mg/kg/day based on body surface area). Oral administration of methylnaltrexone for 104 weeks did not produce tumors in mice and rats.

Mutagenesis

Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test.

Impairment of Fertility

Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the MRHD of 0.2 mg/kg/day based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology

In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone bromide caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 μΜ concentrations, respectively). Methylnaltrexone bromide had a hERG IC₅₀ of > 1000 μΜ. In isolated dog Purkinje fibers, methylnaltrexone bromide caused prolongations in action potential duration (APD). The highest tested concentration (10 μΜ) in the dog Purkinje fiber study was about 18 and 37 times the C_max at human subcutaneous (SC) doses of 0.3 and 0.15 mg/kg, respectively. In isolated rabbit Purkinje fibers, methylnaltrexone bromide (up to 100 μΜ) did not have an effect on APD, compared to vehicle control. The highest methylnaltrexone bromide concentration (100 μΜ) tested was about 186 and 373 times the human C_max at SC doses of 0.3 and 0.15 mg/kg, respectively. In anesthetized dogs, methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at > 1 mg/kg. In conscious dogs, methylnaltrexone bromide caused a dose-related increase in QTc interval. After a single intravenous dosage of 20 mg/kg to beagle dogs, predicted C_max and AUC values were approximately 482 and 144 times, respectively, the exposure at human SC dose of 0.15 mg/kg and 241 times and 66 times, respectively, the exposure at a human SC dose of 0.3 mg/kg. In conscious guinea pigs, methylnaltrexone caused mild prolongation of QTc (4% over baseline) at 20 mg/kg, intravenous. A thorough QTc assessment was conducted in humans [see Clinical Pharmacology (12.2)].

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing occurred at dosages of 3 and 10 mg/kg/day (about 2.4 and 8 times, respectively, the MRHD of 0.2 mg/kg/day based on body surface area). Similar adverse clinical signs were seen in adult rats at 20 mg/kg/day (about 16 times the MRHD of 0.2 mg/kg/day based on body surface area). Juvenile rats were found to be more sensitive to the toxicity of methylnaltrexone bromide when compared to adults. The no observed adverse effect levels (NOAELs) in juvenile and adult rats were 1 and 5 mg/kg/day, respectively (about 0.8 and 4 times respectively, the MRHD of 0.2 mg/kg/day based on body surface area).

Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs. Following intravenous administration of methylnaltrexone bromide for 13 weeks, decreased heart rate (13.2% reduction compared to pre-dose) in juvenile dogs and prolonged QTc interval in juvenile (9.6% compared to control) and adult (up to 15% compared to control) dogs occurred at 20 mg/kg/day (about 54 times the MRHD of 0.2 mg/kg/day based on body surface area). Clinical signs consistent with effects on the CNS (including tremors and decreased activity) occurred in both juvenile and adult dogs. The NOAELs in juvenile and adult dogs were 5 mg/kg/day (about 14 times the MRHD of 0.2 mg/kg/day based on body surface area).

14 CLINICAL STUDIES

14.1 Opioid- Induced Constipation in Adult Patients with Chronic Non-Cancer Pain

The efficacy and safety of RELISTOR® tablets in the treatment of opioid-induced constipation in patients with chronic non-cancer pain were evaluated in a randomized, double-blind, placebo-controlled study (Study 1). This study compared 4- week treatment of RELISTOR® 450 mg orally once daily with placebo.

A total of 401 patients (200 RELISTOR® 450 mg once daily, 201 placebo) were enrolled and treated in the double-blind period. Patients had a history of chronic non-cancer pain for which they were taking opioids. The primary pain condition requiring opioid use was back pain. Other frequently occurring primary pain conditions were arthritis, neurologic/neuropathic pain, joint/extremity pain, and fibromyalgia. Prior to screening, patients had been receiving opioid therapy for pain for > 1 month (median daily baseline oral morphine equivalent dose = 156 mg) and had opioid- induced constipation (< 3 spontaneous bowel movements per week during the screening period). Constipation due to opioid use had to be associated with 1 or more of the following: A Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements (BM), straining during at least 25% of the BMs or a sensation of incomplete evacuation after at least 25% of the BMs.

Patients were required to be on a stable opioid regimen (daily dose > 50 mg of oral morphine equivalents per day) for at least 2 weeks before the screening visit and received their opioid medication during the study as clinically needed. The mean patient age was 51 years, 62% were female, and 82% of patients were Caucasian.

Eligible patients were required to discontinue all previous laxative therapy and use only the study-permitted rescue laxative (bisacodyl tablets). If patients did not have a bowel movement for 3 consecutive days during the study, they were permitted to use rescue medication (up to 3 bisacodyl tablets taken orally once during a 24-hour period). Bisacodyl tablets were taken > 5 hours and < 8 hours after study drug administration. If rescue treatment with bisacodyl tablets did not result in a bowel movement, a second dose of bisacodyl or an enema 24 hours after rescue was permitted. Enema use was permitted after rescue with bisacodyl tablets had failed at least once.

The primary endpoint was the average percentage of dosing days that resulted in spontaneous bowel movements (SBMs) within 4 hours of dosing during Weeks 1 to 4. A SBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours. Table 7 presents the average percentage of patients who responded during the double-blind once daily treatment period in the intent-to-treat (ITT) population, which included all randomized patients who received at least one dose of double-blind study medication.

As shown in Table 24, 27% of patients in the RELISTOR® 450 mg treatment group responded compared to 18% in the placebo treatment group during the 4- week double-blind once daily treatment period. Table 24: Primary Endpoint by Oral Treatment Group in the ITT Population

Percent

Difference^'

Endpoint Treatment N Mean

(2-sided value 95% CI)

Average percentage RELISTOR® 200 27%

dosing days that 450 mg tablets

resulted in SBMs once daily < within 4 hours of 201 18%

0.0001 dosing during Placebo

Weeks 1 - 4

CI = confidence interval; ITT = intent-to-treat

difference for active treatment vs. placebo;

bFrom ANCOVA model with treatment as effect and analysis region as covariate

The responder endpoint was the proportion of patients who responded during Weeks 1 to 4, where a responder is defined as > 3 SBMs/week, with an increase of > 1 SBM/week over baseline, for > 3 out of the first 4 weeks of the treatment period. Table 8 presents the proportion of patients who responded during the double-blind treatment period in the intent- to-treat (ITT) population, which included all randomized patients who received at least one dose of double-blind study medication.

As shown in Table 25, 52% of patients in the RELISTOR® 450 mg once daily treatment group responded compared to 38% in the placebo treatment group during the 4- week double-blind period.

Table 25: Responder Endpoint by Oral Treatment Group in the ITT Population

Percent

Difference³ P-

Endpoint Treatment N n (%)

(2-sided 95% value^b CI)

Proportion of RELISTOR 200 103

patients with >3 450 mg tablets (52%)

13%

SBMs/week during once daily 0.0052

(4%, 23%)

the double-blind 201 77

period * Placebo (38%)

CI = confidence interval; ITT = intent-to-treat;

difference for active treatment vs. placebo;

bBased on logistic regression model with treatment as effect and analysis region as a covariate

With > 1 RFBM/week increase from baseline for > 3 weeks of Weeks 1-4. The efficacy and safety of RELISTOR® subcutaneous injection in the treatment of opioid-induced constipation in patients with chronic non-cancer pain were evaluated in a randomized, double-blind, placebo-controlled study (Study 2). This study compared 4- week treatment of RELISTOR® 12 mg once daily with placebo.

A total of 312 patients (150 RELISTOR® 12 mg once daily, 162 placebo) were enrolled and treated in the double-blind period. Patients had a history of chronic non-cancer pain for which they were taking opioids. The majority of patients had a primary diagnosis of back pain; other primary diagnoses included joint/extremity pain, fibromyalgia, neurologic/neuropathic pain, and rheumatoid arthritis. Prior to screening, patients had been receiving opioid therapy for pain for > 1 month (median daily baseline oral morphine equivalent dose = 161 mg) and had opioid-induced constipation (< 3 spontaneous bowel movements per week during the screening period). Constipation due to opioid use had to be associated with 1 or more of the following: A Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements (BM), straining during at least 25% of the BMs or a sensation of incomplete evacuation after at least 25% of the BMs.

Patients were required to be on a stable opioid regimen (daily dose > 50 mg of oral morphine equivalents per day) for at least 2 weeks before the screening visit and received their opioid medication during the study as clinically needed. The median duration of opioid- induced constipation at baseline was 59 months (4.9 years). The median patient age at baseline was 49 years, 62% were females and 90% were Caucasian.

Eligible patients were required to discontinue all previous laxative therapy and use only the study-permitted rescue laxative (bisacodyl tablets). If patients did not have a bowel movement for 3 consecutive days during the study, they were permitted to use rescue medication (up to 4 bisacodyl tablets taken orally once during a 24-hour period). Rescue laxatives were prohibited until at least 4 hours after taking an injection of study medication.

The primary endpoint was the proportion of patients with > 3 spontaneous bowel movements (SBMs) per week during the 4-week double-blind period. A SBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours. Table 26 presents the proportion of subjects with weekly SBM rate > 3 during the double-blind treatment period in the modified intent-to-treat (mITT) population, which included all randomized subjects who received at least one dose of double-blind study medication. As shown in Table 26, 59% of subjects in the RELISTOR® 12 mg once daily treatment group had > 3 SBMs/week compared to 38% in the placebo treatment group during the 4- week double-blind period.

Table 26: Primary Endpoint by Subcutaneous Injection Treatment Group in the mITT Population

Percent

Endpoint Treatment N n (%) Difference³

(2-sided 95% value CI)

Proportion of RELISTOR 12 mg 150 88

patients with >3 injection once (59%)

SBMs/week during daily < 0.001 the double-blind 162 62

period Placebo (38%)

CI = confidence interval; mITT = modified intent-to-treat;

difference for active treatment vs. placebo;

bp-Value for active treatment vs. placebo based on 2-sided Chi-square test.

Following the first dose, 33% of patients in the RELISTOR® 12 mg once daily treatment group had a SBM within 4 hours and approximately half of patients had a SBM prior to the second dose of RELISTOR®.

14.2 Opioid-Induced Constipation in Adult Patients with Advanced Illness

The efficacy and safety of RELISTOR® in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced illness and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either < 3 bowel movements in the preceding week or no bowel movement for > 2 days). Patients were on a stable opioid regimen > 3 days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication.

Study 4 compared a single, double-blind, subcutaneous dose of RELISTOR® 0.15 mg/kg, or RELISTOR® 0.3 mg/kg versus placebo. The double -blind dose was followed by an open-label 4-week dosing period, where RELISTOR® could be used as needed, no more frequently than 1 dose in a 24 hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR® 0.15 mg/kg, 55 RELISTOR® 0.3 mg/kg, 52 placebo) were enrolled and treated in the double- blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR®-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p < 0.0001 for each dose versus placebo.

Study 5 compared double-blind, subcutaneous doses of RELISTOR given every other day for 2 weeks versus placebo. Patients received opioid medication > 2 weeks prior to receiving study medication. During the first week (days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR® or placebo. In the second week the patient's assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient's assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR®, 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR®-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p < 0.0001). RELISTOR®-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p < 0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR®.

In both studies, there was no evidence of differential effects of age or gender on safety or efficacy. No meaningful subgroup analysis could be conducted on race because the study population was predominantly Caucasian (88%). Durability of Response

Durability of response was explored in Study 5, and the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2- week, double-blind period.

The efficacy and safety of methylnaltrexone bromide was also demonstrated in open- label treatment administered from Day 2 through Week 4 in Study 4, and in two open-label extension studies (Study 4EXT and Study 5EXT) in which RELISTOR® was given as needed for up to 4 months. During open-label treatment, patients maintained their regular laxative regimen. A total of 136, 21, and 82 patients received at least 1 open-label dose in Studies 4, 4EXT, and 5EXT, respectively. Laxation response was also explored in this open- label setting and appeared to be maintained over the course of 3 to 4 months of open-label treatment.

Opioid Use and Pain Scores

No relationship between baseline opioid dose and laxation response in methylnaltrexone bromide-treated patients was identified in exploratory analyses of these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either RELISTOR®-treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either the methylnaltrexone bromide or placebo-treated patients.

17 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration

• Be within close proximity to toilet facilities once RELISTOR® is administered.

• Discontinue RELISTOR® if treatment with the opioid pain medication is also discontinued.

• Re-evaluate the continued need for RELISTOR when the opioid regimen is

changed to avoid adverse reactions.

• In patients with chronic non-cancer pain and opioid-induced constipation: o Discontinue all maintenance laxative therapy prior to initiation of

RELISTOR®. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR® after three days.

Tablets

Advise patients with chronic non-cancer pain receiving RELISTOR® for opioid- induced constipation to:

• Take RELISTOR® tablets once daily with water on an empty stomach at least 30 minutes before the first meal of the day.

Subcutaneous Injection

Advise all patients to:

• Inject RELISTOR® subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

• Safely dispose of needles by following the sharps disposal recommendations

described in the RELISTOR® Instructions for Use.

Advise chronic non-cancer pain patients receiving RELISTOR® for opioid-induced constipation to:

• Inject one dose every day.

Advise patients with advanced illness receiving RELISTOR® for opioid-induced constipation to:

• Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Gastrointestinal Perforation

Advise patients to discontinue RELISTOR® and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain [see Warnings and Precautions (5.1)] .

Severe or Persistent Diarrhea

Advise patients to discontinue RELISTOR® if they experience severe or persistent diarrhea. Opioid Withdrawal

Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR®, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

1.1.1 Pregnancy

Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR® during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

1.1.2 Nursing

Advise females who are nursing against breastfeeding during treatment with RELISTOR® due to the potential for opioid withdrawal in nursing infants.

One skilled in the art will readily ascertain the essential characteristics of the invention and understand that the foregoing description and Examples are illustrative of practicing the provided invention. Those skilled in the art will be able to ascertain using no more than routine experimentation, many variations of the detail presented herein can be made to the specific embodiments of the invention described herein without departing from the spirit and scope of the present invention.

Claims

CLAIMS What is claimed is:

1. A method of treating opioid- induced constipation in a subject, comprising: administering to the subject a pharmaceutical composition comprising a compound of formula (II):

II wherein A^" comprises a suitable anion, and

wherein the administration of the pharmaceutical composition results in a rescue free bowel movement and reduces the risk of a cardiovascular event in the subject.

2. A method of decreasing the risk of a cardiovascular event in a subject having opioid induced constipation, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (II):

II wherein A^" comprises a suitable anion, and

wherein the administration of the pharmaceutical composition reduces the risk of a cardiovascular event in the subject.

3. The method of claim 2, wherein administration of the pharmaceutical composition results in a rescue free bowel movement and/or improved stool consistency, thereby reducing the risk of a cardiovascular event in the subject.

4. A method of increasing compliance with opioid treatment in a subject having opioid induced constipation, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (II):

II wherein A^" is a suitable anion, and

wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of of symptoms of opioid withdrawal.

5. A method of treating opioid-induced constipation in a subject, comprising: administering to the subject a pharmaceutical composition comprising a compound of formula (II):

II wherein A^" comprises a suitable anion, and

wherein the subject is suffering from hepatic impairment.

6. The method of claim 5, wherein the subject has Child-Pugh Class B or Class C hepatic impairment.

7. A method of treating opioid-induced constipation in a subject, comprising: administering to the subject a pharmaceutical composition comprising a compound of formula (II):

II wherein A^" comprises a suitable anion, and

wherein the subject is suffering from renal impairment.

8. The method of claim 7, wherein the subject has a renal clearance rate of CIR = 52 + 28 mL/min.

9. The method of claim 7, wherein the subject has a creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault.

10. The method of any one of claims 1 to 9, wherein A- comprises an anion of the amphiphilic pharmaceutically acceptable excipient.

11. The method of any one of claims 1 to 9, herein the subject has advanced illness and is receiving palliative care.

12. The method of any one of claims 1 to 9, wherein the subject's response to laxative therapy has not been sufficient.

13. The method of any one of claims 1 to 9, wherein the subject has advanced chronic pain.

14. The method of any one of claims 1 to 9, wherein the subject has chronic non- malignant pain.

15. The method of claim 14, wherein the subject has had chronic non-malignant pain for at least 2 months prior to administration of the pharmaceutical composition.

16. The method of any one of claims 1 to 9, wherein the method increases compliance with opioid treatment in a subject having opioid induced constipation.

17. The method of any one of claims 1 to 9, wherein the subject thereby reduces the risk of opioid withdrawal.

18. The method of claim 17, wherein the risk of opioid withdrawal comprises risk of having one or more withdrawal symptoms.

19. The method of claim 17, wherein the subject thereby reduces the risk of having one or more withdrawal symptoms.

20. The method of any one of claims 1 to 3, wherein the risk of a cardiovascular event in the subject is reduced due to a reduction in straining.

21. The method of any one of claims 1 to 3, wherein the risk of a cardiovascular event in the subject is reduced due to the subject's ability to maintain optimal opioid pain management.

22. The method of any one of claims 1 to 3, wherein the cardiovascular event is at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.

23. The method of any one of claims 1 to 3, wherein the cardiovascular event is at least one selected from the group of: elevated pulse, stroke, changes in blood pressure, changes in systolic blood pressure and changes in diastolic blood pressure.

24. The method of any one of claims 1 to 9, wherein the subject is also administered opioids.

25. The method of claim 24, wherein the administering of the pharmaceutical composition comprising a compound of formula (II) is not followed by an adjustment of administration of the opioid in the subject.

26. The method of claim 25, wherein the administering of the pharmaceutical composition does not lead to an adjustment of the dosage of opioid administered to the subject.

27. The method of claim 26, wherein the administering of the pharmaceutical composition is not followed by an increase in the dosage of the opioid administered to the subject.

28. The method of any one of claims 1 to 9, wherein the administering of the pharmaceutical composition is not followed by an increase in pain intensity experienced by the subject.

29. The method of any one of claims 1 to 9, wherein A^" comprises an anion selected from the group consisting of: chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate.

30. The method of claim 29, wherein A^" comprises bromide.

31. The method of claim 10, wherein A^" comprises an anion selected from the group consisting of: butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulphate.

32. The method of any one of claims 1 to 9, wherein A^" comprises bromide and dodecyl (lauryl) sulfate.

33. The method of any one of claims 1 to 9, wherein the pharmaceutical composition further comprises at least one agent selected from the group consisting of sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof.

34. The method of any one of claims 1 to 9, wherein the pharmaceutical composition further comprises at least one agent selected from the group consisting of colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscarmellose sodium, poloxamer 407, siliconized microcrystalline cellulose, stearic acid and combinations thereof.

35. The method of any one of claims 1 to 9, wherein the pharmaceutical composition dosage form is a tablet.

36. The method of any one of claims 1 to 9, wherein the administering comprises orally administering from about 150 mg to about 450 mg of methylnaltrexone, or a salt thereof.

37. The method of claim 36, wherein the administering comprisies orally administering about 150 mg, about 300 mg, or about 450 mg of methylnaltrexone, or a salt thereof.

38. The method of claim 36, wherein the methylnaltrexone is administered as one or more tablets, wherein each tablet comprises about 150 mg of methylnaltrexone.

39. The method of any one claims 1 to 9, wherein the subject has been receiving opioid treatment prior to administration of the pharmaceutical composition.

40. The method of claim 39, wherein the subject has been receiving opioid treatment for at least one month.

41. The method of claim 40, wherein the subject has been receiving opioid treatment comprising at least 50 mg of oral morphine equivalents per day for at least 14 days.

42. The method of any one of claims 1 to 9, wherein the subject will start opioid treatment in less than 1, 2, 3 or 4 weeks.

43. The method of any one of claims 1 to 9, wherein the subject has had opioid induced constipation for at least 30 days.

44. The method of any one of claims 1 to 9, wherein the subject has experienced less than 3 rescue free bowel movements per week for at least four consecutive weeks.

45. The method of any one of claims 1 to 9, wherein the subject has experienced straining during bowel movements.

46. The method of any one of claims 1 to 9, wherein the administering results in a rescue free bowel movement within 4 hours of administration of the pharmaceutical composition.

47. The method of any one of claims 1 to 9, wherein the administering results in an increase of at least one rescue free bowel movement per week as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.

48. The method of claim 47, wherein the administering results in an increase of at least 2, 3, 4 or 5 rescue free bowel movements per week.

49. The method of any one of claims 1 to 9, wherein the administering results in an increase of at least one rescue free bowel movement per week for each of the first 4 weeks of daily administration of the pharmaceutical composition.

50. The method of any one of claims 1 to 9, wherein the administering results in improved stool consistency.

51. The method of any one of claims 1 to 9, wherein the subject experiences at least 3 rescue free bowel movements in each of the first 4 weeks of daily administration of the pharmaceutical composition; and the subject experiences an increase of at least one rescue free bowel movement per week for at least 3 of the first 4 weeks of daily administration as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.

52. The method of claim 36, wherein the administering comprises orally administering about 150 mg of methylnaltrexone, or a salt thereof.

53. The method of claim 36, wherein the administering comprises orally administering about 300 mg of methylnaltrexone, or a salt thereof.

54. The method of any one of claims 1 to 9, wherein administration of the pharmaceutical composition does not result in any clinically significant drug-drug interactions.

55. The method of any one of claims 1 to 9, wherein administration of the pharmaceutical composition demonstrates minimal interaction with CYP enzymes and/or drug transporters.