RU2571268C2 - Modulation of systemic effect of rifaximin - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to the influence of liver failure on rifaximin pharmacokinetics. Described application of rifaximin for obtaining a medication for the treatment of a subject, suffering from, subjected to or being at a stage of remission of hepatic encephalopathy (HE), which includes the introduction of rifaximin during the period from approximately 24 weeks to 24 months in a dose of 550 mg twice per day daily.

EFFECT: medication makes it possible to reduce a risk of expressed hepatic encephalopathy in the subject.

6 cl, 19 tbl, 6 dwg, 4 ex

Description

RELATED APPLICATIONS

This application claims the priority of provisional application US No. 61/187251, registered June 15, 2009, and provisional application US No. 61/297696, registered January 22, 2010. A full description of each of these is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, such as pyrido-imidazo-rifamycin. Rifaximin has been reported to be characterized by negligible systemic absorption due to its chemical and physical properties ( Descombe JJ et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994 ) ).

Rifaximin is described in Italian patent IT 1154655 and EP 0161534, both of which are fully incorporated herein by reference in all respects. EP 0161534 describes a method for producing rifaximin using rifamycin O as a starting material (The Merck Index, XIII Ed., 8301).

SUMMARY OF THE INVENTION

This document presents the discovery that rifaximin exhibits different pharmacokinetics in subjects with hepatic impairment when compared with subjects with a normal hepatic system. Accordingly, in one aspect, provided herein are methods for increasing the systemic exposure of rifaximin (AUCtau) in a subject after oral administration by selecting a subject with hepatic insufficiency, and oral administration of rifaximin to a subject where the systemic exposure of rifaximin is increased in a subject with liver failure compared to subject without liver failure.

In a corresponding embodiment, the subject with liver failure has a liver disease end-stage model index (MELD) of less than 11 for that subject. In another appropriate embodiment, the liver-deficient subject has a liver disease end-stage model index (MELD) in the range of 11 to 18 for that subject.

In another embodiment of the invention, the subject suffering from liver failure has an A (mild hepatic impairment) score according to the Child-Pugh A classification. In another embodiment of the invention, the subject suffering from liver failure has an indicator of B (chronic alcoholic liver damage) according to the Child-Pugh B classification.

In another embodiment, the systemic effect of rifaximin in a subject suffering from liver failure includes an effect of at least 5 times that of a subject without liver failure. In another embodiment, the systemic effect of rifaximin in a subject suffering from liver failure includes an effect of at least 9.6 times that in a subject without liver failure. In another embodiment, the systemic effect of rifaximin in a subject suffering from liver failure includes an effect of at least 13.1 times that in a subject without liver failure. In another embodiment, the systemic effect of rifaximin in a subject suffering from liver failure includes exposure exceeding from about 5 to about 13.1 times that of a subject without liver failure.

In one particular embodiment, a subject suffering from liver failure has hepatic encephalopathy.

In another embodiment, the methods provided herein further include administering rifaximin with food.

In one embodiment, ingestion delays the time to reach maximum plasma concentration.

In another embodiment, the methods provided herein further include selecting a subject exposed to or suffering from diarrhea of travelers.

In another appropriate embodiment, the methods provided herein further include informing the subject that the elimination rate of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure.

In another aspect, provided herein are methods for increasing a plasma rifaximin concentration (C _max ) in a subject after oral administration, by selecting a subject with hepatic insufficiency, and orally administering rifaximin to a subject having hepatic insufficiency, where plasma rifaximin concentrations are elevated in a subject with liver failure compared with a subject without liver failure.

In one embodiment, a subject suffering from liver failure has an elevated level of alanine aminotransferase (ALT).

In one embodiment, the concentration of rifaximin in the blood plasma of a subject suffering from liver failure includes an effect of at least 2 times that of a subject without liver failure.

In another embodiment, the methods provided herein further include administering rifaximin with food, thereby delaying the time to reach maximum plasma concentration.

In another embodiment of the invention, the methods further comprise selecting a subject subject to or suffering from diarrhea of travelers.

In another appropriate embodiment, the methods provided herein further include informing the subject that the elimination rate of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure.

In another aspect, provided herein are methods of reducing the rate of elimination of rifaximin in a subject after oral administration by selecting a subject having hepatic insufficiency and orally administering rifaximin to a subject having hepatic insufficiency, where the rate of elimination of rifaximin is reduced in a subject with hepatic insufficiency compared with a subject without liver failure.

In one embodiment, the elimination rate of rifaximin is reduced by at least 25% in a subject with liver failure compared to a subject without liver failure.

In another embodiment of the invention, the subject suffering from liver failure has an A (mild hepatic impairment) score according to the Child-Pugh A classification. In another embodiment of the invention, the subject suffering from liver failure has an indicator B (chronic alcoholic liver damage) according to the Child-Pugh B classification.

In another embodiment, reducing the elimination rate further includes increasing the bioavailability of rifaximin in a subject with liver failure.

In another embodiment, the subject suffering from liver failure is a subject having at least one sign, symptom or episode of hepatic encephalopathy or at least one portosystemic anastomosis. In another embodiment, the subject is susceptible to or suffering from diarrhea of travelers.

In another appropriate embodiment, the methods provided herein further include informing the subject that the elimination rate of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure.

In another aspect, provided herein are methods for determining a therapeutically effective dose of rifaximin for a subject, by selecting a subject having hepatic encephalopathy, and determining a therapeutically effective dose, taking into account the subject having hepatic encephalopathy.

In one embodiment of the invention, the subject has or is subject to diarrhea of travelers.

In another embodiment, a dose is administered to a subject that is increased compared to a dose administered to a subject that does not have or is not prone to hepatic encephalopathy.

In another embodiment, a dose is administered to a subject that is reduced compared to a dose administered to a subject who does not have or is not prone to hepatic encephalopathy.

In another embodiment, the methods further include informing the subject of one or more of the following: the rate of elimination of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure; the systemic effect of rifaximin is increased in a population of subjects with liver failure compared with a population of subjects without liver failure, the concentration of rifaximin in blood plasma is increased in a population of subjects with liver failure compared with a population of subjects without liver failure, and / or the clearance rate of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure.

In another aspect, provided herein are methods for determining a therapeutically effective dose of rifaximin for a subject by selecting a subject having or susceptible to liver failure, comprising

establishing a relationship of liver failure with at least one of the increased systemic exposure to rifaximin, an increased concentration of rifaximin in the blood plasma, or a reduced clearance rate of rifaximin, and

determining a therapeutically effective dose, taking into account one or more of the increased systemic exposure to rifaximin, an increased concentration of rifaximin in the blood plasma, or a reduced rate of rifaximin clearance in a subject associated with liver failure.

In another embodiment of the invention, the subject suffering from liver failure has a Child-Pugh A. score. In another embodiment, the subject suffering from liver failure has a Child-Pugh B. score.

In a corresponding embodiment, the subject has a liver disease end-stage model index (MELD) of less than 11. In another relevant embodiment, a subject suffering or suffering from liver failure has a liver-disease end-stage model index (MELD) in the range of 11 to 18.

In another aspect, the subject has an elevated ALT level.

In another aspect, the subject has at least one portosystemic anastomosis. In another embodiment, the subject already had at least one episode of hepatic encephalopathy. In another embodiment, the subject already had at least one episode of hepatic encephalopathy in the previous six months. In another embodiment, the subject already had at least two episodes of hepatic encephalopathy in the previous six months.

In another embodiment, the methods further include selecting a subject subject to or suffering from diarrhea of travelers.

In another aspect, provided herein are methods for determining a therapeutically effective dose of rifaximin for a subject, comprising:

selection of a subject having or susceptible to liver failure,

establishing a relationship of liver failure with at least one of the increased systemic exposure to rifaximin, an increased concentration of rifaximin in the blood plasma, or a reduced clearance rate of rifaximin, and

determining a therapeutically effective dose, taking into account at least one of the increased systemic exposure to rifaximin, an increased concentration of rifaximin in the blood plasma, or a reduced rate of rifaximin clearance in a subject associated with liver failure.

In another aspect, provided herein are methods for treating traveler's diarrhea (TD) by selecting a subject suffering or suffering from diarrhea of travelers, instructing the subject to orally administer rifaximin, and informing the subject about one or more of: the elimination rate of rifaximin is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure; systemic exposure to rifaximin is increased in a population of subjects with liver failure compared with a population of subjects without liver failure; plasma rifaximin concentrations are increased in a population of subjects with liver failure compared with a population of subjects without liver failure; and / or rifaximin clearance rate is reduced in a population of subjects with liver failure compared with a population of subjects without liver failure.

In another embodiment of the invention, the subject suffering from liver failure has a Child-Pugh A. score. In another embodiment, the subject suffering from liver failure has a Child-Pugh B. score.

In a corresponding embodiment, the subject has a liver disease end-stage model index (MELD) of less than 11. In another corresponding embodiment, the liver deficient subject has a liver disease end-stage model index (MELD) in the range of 11 to 18.

In a corresponding embodiment, hepatic failure includes hepatic encephalopathy.

In another embodiment of the invention, the methods further include identifying subjects having liver failure. In a corresponding embodiment of the invention, the methods further comprise examining the subjects for liver failure.

In another embodiment of the invention, the methods further include varying the amount of rifaximin administered based on a subject having liver failure compared to a subject without liver failure.

In another embodiment of the invention, the methods further include changing the dosage regimen of rifaximin based on a subject having liver failure compared with a subject without liver failure.

In another embodiment of the invention, the methods further include informing the subject that the systemic exposure to rifaximin and / or plasma rifaximin concentration changes with food intake.

In another aspect, provided herein are kits comprising rifaximin, or a pharmaceutical composition thereof, and instructions for administration to a subject with liver failure. In one embodiment, the kit includes instructions for administering rifaximin to a subject having hepatic encephalopathy.

Other embodiments of the invention and aspects are discussed below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the mean + SD of the plasma rifaximin concentration versus time curves on a linear scale.

In FIG. Figure 2 shows the time to the first spontaneous expressed episode of HE in a subgroup.

In FIG. Figure 3 shows the results of Twa of the total score and individual CLDQ domain in the treatment group (ITT population).

In FIG. Figure 4 shows the Twa results of the total score and individual CLDQ domain for spontaneous expressed HE status.

In FIG. Figure 5 shows a comparative analysis of the Kaplan-Meier survival estimate for time to the first spontaneous episode of HE expressed. A placebo study was shown compared with a rifaximin study in subjects in a cross-site study up to 6 months of treatment.

In FIG. Figure 6 shows the average values of PSE values at the beginning and at the end of the course of treatment in clinical trials.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Embodiments of the invention provided herein relate to detecting differences in systemic exposure, plasma concentrations, and constant maximum elimination rate of rifaximin in a subject suffering from liver failure compared with a subject having normal liver function. In addition, the invention relates to the detection of the effect of food intake on reaching the maximum plasma concentrations of rifaximin in a subject's blood plasma.

The main pathogenesis of HE is associated with nitrogen-containing substances of intestinal origin that adversely affect brain function. Ammonia, a byproduct of protein breakdown, which normally detoxifies in the liver, is believed to be the most important of these compounds. The correlation of blood levels with the mental state of cirrhosis, however, is unreliable, in part, since the permeability of the blood-brain barrier to ammonia is increased in patients with HE. Other intestinal toxins have also been considered as HE conditioning agents.

In patients with chronic liver disease, the occurrence of hepatic encephalopathy is associated with poor quality of life compared with age-matched patients without HE. Severe episodes of HE deplete the body, can occur suddenly, lead the patient to a state of inability to self-care, and often lead to hospitalization. In patients with HE, symptoms appear, including fatigue, daytime drowsiness, and a lack of report in their own actions (Conn indicator is 1); and confusion and disorientation (Conn score is 2), which significantly interfere with everyday function and reduce the ability to self-service. Often, this lack of self-care ability leads to malnutrition and non-compliance with the therapy and subsequently leads to more severe symptoms, such as increased doubtfulness, complete disorientation and stupor (Conn indicator is 3) or coma (Conn indicator is 4).

The history of severe HE episodes and the severity of the episodes have been found to be prognostic factors in the decreased survival of patients with chronic liver disease. In patients with cirrhosis and a history of severe HE episodes, survival was 42% for 1 year and 23% for 3 years after the onset of HE. In another analysis, the appearance of an HE episode with a Conn score of 2 in patients with cirrhosis was associated with a 4-fold increased risk of death.

These toxic compounds gain access to systemic circulation as a result of decreased liver function or portosystemic anastomoses. Once in the brain tissue, these compounds cause changes in neurotransmission, which affects consciousness and behavior. HE is explained by global inhibition of the action of the central nervous system from nitrogen-containing compounds, which leads to the excitation of gamma-aminobutyric acid (GABA) and reduced glutamate neurotransmission.

Triggering factors include azotemia (29%), sedatives, tranquilizers, analgesics (24%), gastrointestinal bleeding (18%), excess protein (9%), metabolic alkalosis (11%), infection (3%), constipation (3%). Surgery, in particular, transhepatic intrahepatic portosystemic shunting (TIPS) procedures, can also provoke HE. The occurrence of HE for unknown reasons is only 2% of cases.

The initial manifestations are subclinical and require psychometric testing to make a diagnosis. There are 4 progressive stages of the lesion, known as the West Haven criteria (or Conn score), ranging from stage 0 (no detectable changes in the individual) to stage 4 (coma, decerebral posture, dilated pupils), as discussed in more detail below.

HE is manifested in the form of continuous psychomotor dysfunction, impaired memory, increased reaction time, sensory disturbances, poor concentration and, in severe forms, in the form of a coma. Changes can affect individual personality traits, consciousness, behavior and neuromuscular function. Neurological symptoms may include hyperreflexia, rigidity, myoclonic cramps and asterixis (sweeping “clapping” muscle tremors). Performing cognitive tasks, such as connecting numbers with lines, may be impaired. Hepatic breath may occur (sweet smell of exhaled breath). Electroencephalogram curves (EEGs) show a nonspecific, slow, three-phase wave activity above the frontal lobes. The prothrombin time can be lengthened and cannot be corrected with vitamin K. Computed tomography of the head can show a normal picture or general atrophy. Finally, signs of liver disease such as jaundice and ascites can be seen.

The diagnosis of HE is made on the basis of an anamnesis and verification of physical and mental state by clinical units that are aware of existing liver disease, provoking factor (s) and / or previous history of HE. EEG can exhibit short-wave activity even with mild disease. Elevated serum ammonia is a characteristic feature, but not a necessary factor, and weakly correlates with the level of encephalopathy.

Treatment of patients with chronic HE includes 1) providing symptomatic therapy, 2) identifying and eliminating provoking factors, 3) reducing the nitrogen-containing load from the intestine, and 4) assessing the need for long-term therapy. Nitrogen-containing load from the intestine, as a rule, reduce the use of non-absorbable disaccharide (lactulose) and / or antibiotics.

Lactulose is considered the primary treatment in the United States, but is currently not approved in the United States to either treat or prevent HE. Lactulose is metabolized by intestinal intestinal bacteria, which leads to a lower pH value of feces, a laxative effect and, ultimately, the release of feces. Lower pH ionizes ammonia (NH ₃ ) to ammonium ion (NH ₄ ⁺ ), which is used by bacteria for amino acid and protein synthesis. This reduces serum ammonia levels and improves mental function.

Conventional therapy is aimed at reducing the production and absorption of ammonia. Lactulose is usually used in doses of 30-60 g daily. However, the dose can be increased to 20-40 g of TID-QID to cause 2-3 half-formed bowel movements per day. If lactulose cannot be administered orally or through a nasogastric tube, for example, to patients with stage 3 or 4 HE, it can be administered as 300 cm ³ (200 g) of a holding enema.

In acute encephalopathy, lactulose can be administered either orally, through the mouth or through a nasogastric tube, or through a holding enema. The standard dose for oral administration is 30 g, followed by dosing every 1-2 hours, until the release of feces. From this point on, dosing is selected to achieve two or three soft bowel movements per day.

Lactulose is released without a prescription. A convenient and relatively tasteless dosage form, often referred to in the trade as “lactulose powder for oral solution”, can be obtained, for example, from Bertek Pharmaceuticals, Sugarland, Tex. as Kristalose ^RTM in 10 and 20 g packages. Lactulose syrups commonly marketed as laxatives include Cephulac ^RTM , Chronulac ^RTM , Cholac ^RTM and Enulose ^RTM . These syrups can replace lactulose powder by using a sufficient amount of syrup to provide the required dose of lactulose; usually, the listed syrups contain approximately 10 g of lactulose in 15 ml of syrup.

Broad-spectrum antibiotics active against the gastrointestinal tract, including neomycin, metronidazole, vancomycin and paromomycin, have been used with and without lactulose. Current directives recommend neomycin in an amount of 1 to 2 g per day by mouth with periodic monitoring of renal function and annual hearing control or metronidazole in an amount of 250. Lactulose can cause diarrhea, leading to dehydration, which can trigger HE. Additionally, adherence to lactulose is limited to patients disgusted with its overly sweet taste. In addition, the dosage regimen, which is associated with the rhythm of bowel movement and side effects such as flatulence, bloating, diarrhea (which leads to dehydration), and acidosis make it difficult to use lactulose for a long time.

The use of antibiotics in the treatment of HE is difficult due to toxicity associated with prolonged use. In particular, systemic absorption of neomycin, metronidazole and ampicillin has led to rare cases of nephrotoxicity, ototoxicity, staphylococcal enterocolitis ( S. enterocolitis ) and / or the development of resistant bacterial strains. In addition, neomycin inhibits only aerobic bacteria. Metronidazole is metabolized slowly in patients with hepatic dysfunction, has the ability to interact with alcohols (disulfiram-like effect), and high blood levels can lead to paroxysms.

One of the antibiotics specific to the gastrointestinal tract is rifaximin. Rifaximin is not an aminoglycoside, it is a semi-synthetic antibiotic obtained from rifamycin O. It does not have a systemic effect, is not absorbed, has a wide spectrum of action, is an oral antibiotic specific for intestinal pathogens of the gastrointestinal tract. Rifaximin has been found to be preferred in treating HE over previously used antibiotics; for example, a negligible systemic absorption (<0.4%) regarding food intake or the presence of a gastrointestinal disease and the lack of evidence of accumulation in blood plasma at high or repeated doses. The lack of systemic absorption determines the safety and good tolerance of rifaximin, thereby improving the patient's responsiveness and reducing side effects associated with currently known treatment methods.

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, such as pyrido-imidazo-rifamycin. Rifaximin exhibits a wide spectrum of antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria causing infectious diarrhea, irritable bowel syndrome, excessive bacterial growth in the small intestine, Crohn’s disease and / or pancreatic insufficiency. Rifaximin has been reported to be characterized by negligible systemic absorption due to its chemical and physical properties (Descombe JJ et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994 )).

Rifaximin is described in Italian patent IT 1154655 and EP 0161534. Patent EP 0161534 discloses a method for producing rifaximin using rifamycin O as a starting material (The Merck Index, XIII Ed., 8301). US 7,045,620 B1 provides information on polymorphic forms of rifaximin. The applications and patents referred to in this document are fully incorporated herein by reference in all respects.

Embodiments of the invention provided herein also relate to the administration of drugs to a subject in need of treatment with compositions such as rifaximin.

Rifaximin is a compound of the rifamycin class of antibiotics. Rifaximin is a compound having the structure of Formula I:

In one embodiment, rifaximin is a poorly absorbed molecule in certain subjects. This has been shown in clinical pharmacokinetic studies in normal subjects after single and multiple oral dosing, demonstrating that rifaximin is poorly absorbed from the gastrointestinal tract (for example, <1% of this drug is absorbed after oral administration). While trace amounts of the parent drug and metabolites were found in the urine, the release of rifaximin in large quantities with feces was found, mostly unchanged. Upon repeated administration, there was little or no systemic accumulation of the drug, and the time to reach equilibrium was short. It was unexpected that the introduction of a daily dose of 1.5 times higher according to the regimen of taking medications three times a day did not lead to a proportional increase in the total daily systemic exposure to rifaximin; AUC _{Total was} only approximately 13% higher after dosing three times a day than after dosing twice a day.

“Rifaximin,” as used herein, includes solvates and polymorphic forms of a molecule, including, for example, α, β, γ, δ, ε, η, ξ and amorphous forms of rifaximin. These forms are described in more detail, for example, in USSN 11/873841; USSN 11/658702; EP 05004635.2, registered May 03, 2005; USPN 7045620; US 61/031329; and G. C. Viscomi, et al., CrystEngComm, 2008, 10, 1074-1081 (April 2008). A full description of each of these references is incorporated herein by reference.

"Polymorphism", as used herein, refers to the existence of various crystalline forms of a single compound in a particular hydrated state, for example, the property of certain compounds and complexes. Thus, polymorphs are clearly defined solids having the same molecular formula, despite the fact that each polymorph can have certain physical properties. Thus, a single compound can serve as a source of the formation of various polymorphic forms, where each form has different and specific physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, fluidity, compressibility and / or X-ray diffraction peaks. The solubility of each polymorph can vary, so identifying the existence of pharmaceutical polymorphs is essential to provide pharmaceuticals with predictable solubility profiles. It is desirable to investigate all forms of the drug in the solid phase, including all polymorphic forms, and to determine the stability, dissolution and flow characteristics of each polymorphic form. Polymorphic forms of the compound can be distinguished in the laboratory by X-ray diffraction spectroscopy and other methods, such as infrared spectrometry. For a general overview of polymorphs and the pharmaceutical uses of polymorphs, see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), each of which is incorporated herein by reference.

As used herein, the term “systemic exposure” is intended to mean the effects of rifaximin on a subject by its administration and subsequent exposure to rifaximin in the blood plasma of a subject, followed by distribution throughout the body of the subject. Increased systemic exposure can be measured by determining the concentration of rifaximin in the blood plasma of a subject. In illustrative embodiments, increased systemic exposure may result from a decrease in rifaximin clearance.

A combination of pathophysiological factors may explain the increased effects of rifaximin on subjects with a history of HE compared with healthy subjects. Episodes of hepatic encephalopathy as a result of the accumulation in the central nervous system of nitrogen-containing substances of intestinal origin (mainly ammonia) due to portosystemic anastomoses and portal hypoperfusion are associated with cirrhosis. Subjects with mild to moderate impaired liver function and a documented history of episodes of hepatic encephalopathy were included in the study. Hepatic encephalopathy is a complication of cirrhosis due to portal hypertension, cerebral vasodilation, and liver failure. Recent studies have shown a high prevalence of spontaneous portosystemic anastomoses in persistent hepatic encephalopathy.

In chronic liver disease, a significant part of the blood circulation in the portal vein system does not flow through the functional cells of the liver due to the presence of intrahepatic functional anastomoses or extrahepatic anatomical anastomoses. As a result, the presystemic clearance of orally administered substances is reduced, and the systemic bioavailability is increased. Higher rates of rifaximin exposure were apparently due in part to a decrease in presystemic metabolism in the presence of portosystemic anastomoses and / or portal hypoperfusion. This possibility is supported by the fact that although the effect of rifaximin in the blood plasma from the gastrointestinal tract is limited (~ 0.32% of the dose), there is a hypothesis that this small absorbed fraction undergoes first-pass metabolism in healthy subjects (~ 90.6 %), since only a small fraction of rifaximin is excreted unchanged in the urine (0.03% of the dose). In addition, since the terminal t _{1/2 of} rifaximin was clinically statistically significantly longer (approximately 2 times) in subjects with HE relative to healthy subjects, the stronger effect found in HE may result from a decrease in systemic clearance of the drug.

As used herein, a “subject” includes organisms that can suffer from an intestinal disorder or other disorder that can be treated with rifaximin, or which could otherwise benefit from the administration of a rifaximin product as described herein, such as humans and animals other than humans. The term “non-human animals” as provided herein includes all vertebrates, for example, mammals, for example, rodents, for example mice, and non-mammals, such as non-human primates, for example, sheep, dog, cow , chickens, amphibians, reptiles, etc.

An “affected bowel disorder” as used herein includes subjects at risk of developing bowel disturbance, for example, subjects suffering from HE, immunosuppression, subjects who have been in contact with other subjects with a bacterial infection, subjects with a family history of disruption intestines, subjects with a gene profile indicating a disease or risk of developing bowel dysfunction, subjects with a known predisposition to bowel dysfunction doctors, doctors, nurses, subjects traveling to remote areas where bacteria are common that cause travelers' diarrhea, etc.

A subject “suffering from liver failure,” as used herein, includes subjects diagnosed with a clinical decline in liver function, for example, due to hepatic encephalopathy, hepatitis, or cirrhosis. Hepatic insufficiency can be quantified using any of a number of scales, including the End-stage Liver Disease Model Index (MELD), Child-Pugh or Conn.

The MELD index uses the patient's values for serum bilirubin, serum creatinine and the international normalized ratio for prothrombin time (INR) to provide a weighted numerical value for correlation with expected survival. Index 10-19 correlates with 27% mortality over three months, and index <10 correlates with 4% mortality over three months. Methods for determining and analyzing MELD indices are well known in the art.

The Child-Pugh indicator (in some cases, the Child-Turcotte-Pugh indicator) used to assess the prognosis of chronic liver disease, mainly cirrhosis, is a combined indicator of five clinical measurements, bilirubin, serum albumin, INR, ascites and hepatic encephalopathy. Each marker is assigned a value from 1 to 3, and the total value is used to provide an indicator classified as A (5-6 points), B (7-9 points) or C (10-15 points), which may correlate with one and two-year survival. Methods for determining and analyzing Child-Pugh indicators are well known in the art.

Measurements of changes in mental status can be performed, for example, using the Conn indicator (also known as the West Haven indicator). The Conn indicator was widely used as a measure of mental status in the HE study and is based on the Parsons-Smith criteria with Conn changes. Asterixis is not considered in assessing the status of a subject using the criteria for evaluating the Conn indicator listed below.

The scale used in the Conn scorecard is presented below.

Degree 0 = HE identified anomalies in personality traits or behavior

Grade 1 = Trivial lack of perception, euphoria or anxiety; shortened attention span; violation of addition or subtraction

Grade 2 = lethargy; disorientation in time; obvious personality changes; inappropriate behavior

Grade 3 = Somnolence up to a half stop, reacting to stimuli; confused; severe disorientation; freakish behavior

Grade 4 = Coma; lack of ability to undergo mental state testing.

The degree of asterixis (clapping tremor) can be determined in a subject holding both arms and forearms extended with wrists bent up and fingers spread apart for ≥30 seconds. Asterixis was measured along a continuum of 5 degrees, for example, degrees 0 and 4 = no abnormal movement as opposed to almost continuous clapping movements, respectively, as shown below:

Grade 0 = no tremor;

Grade 1 = rare clapping movements;

Grade 2 = occasional, irregular popping involuntary movements;

Grade 3 = frequent popping involuntary movements; and

Grade 4 = almost continuous clapping movements.

Activity activity relative to the degree of asterixis can be measured as the time of any increase in the degree of asterixis from the baseline. The time to increase the degree of asterixis was calculated as the number of days from the first dose of rifaximin to the initial occurrence of an increase in the degree of asterixis from the baseline.

The expression “prophylactically effective amount” of a compound refers to the amount of a compound represented by formula (I) herein or as otherwise described herein that is effective in administering a dose once or repeatedly to a subject to prevent or treat a bacterial infection or HE.

The expression "therapeutically effective amount" refers to the amount of a substance that is effective in a single or multiple dose to a subject to provide a beneficial therapeutic effect to the subject. In another embodiment, the beneficial therapeutic effect is to inhibit a bacterial infection or prolong the survival of a subject with such a bacterial infection beyond what was expected in the absence of such treatment.

Rifaximin exhibits a wide spectrum of antibacterial activity in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, including anaerobic strains. Rifaximin has been reported to be characterized by negligible systemic absorption due to its chemical and physical properties ( Descombe JJ et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994 ) ).

It was found that the presence of liver failure affects the effect of rifaximin in vivo in plasma. Therefore, this is done as a criterion for a healthcare professional (e.g., doctor, physician assistant, paramedic, pharmacist) to consider when prescribing a dose of rifaximin to treat bowel problems, such as travelers' diarrhea or IBS. Hepatic insufficiency leads to a clinically statistically significant increase in rifaximin adsorbed in subjects undergoing treatment. One embodiment of the invention discussed herein is methods of modulating the therapeutic effect of rifaximin by selecting a subject suffering from liver failure and further providing prophylaxis or treatment for liver failure.

Accordingly, one embodiment of the invention is a method for treating traveler's diarrhea (TD) in a subject. In this method, rifaximin is administered to a subject suffering from a disease treatable by rifaximin. The subject is informed that the systemic exposure to rifaximin in blood plasma is increased in subjects suffering from liver failure, compared with subjects not suffering from liver failure. This information enhances the safety of administering rifaximin to a subject. Examples of rifaximin treatable diseases include travelers' diarrhea and hepatic encephalopathy.

As used herein, “information” or “counseling” means a reference to or provision of published or oral material. For example, providing the active substance with published material for the user; or verbally, for example, by presenting at a seminar, conference, or other educational presentation, by communicating between a sales representative of a pharmaceutical company and a healthcare professional, or by communicating between a healthcare provider and a patient; or showing appropriate information to the user for understanding. Examples of health workers include doctors, nurses, and paramedics.

One aspect of the present invention includes providing information to prescribing doctors and patients receiving rifaximin treatment, which is useful for minimizing the safety concerns of rifaximin. In this embodiment of the invention, this information reports that systemic exposure to rifaximin in blood plasma is increased in subjects suffering from liver failure, compared with subjects not suffering from liver failure. In one embodiment of the invention, information is provided on a label. In another embodiment of the invention, the information is presented in the information sheet that is issued to the patient when the rifaximin prescription is filled.

In addition, the method may also include the stage or stages of the distribution of prescribed doses of rifaximin by drugstores or the distribution of training materials to drugstores, including pharmacists with training material that includes information about what the patient needs to know and what the patient should do to avoid any side effects rifaximin when taking a dose.

In addition, the method may include the step or steps of providing pharmacists with guidelines for advising patients on what the patient needs to know and what the patient should do in order to safely use doses of rifaximin. The method may further include a stage requiring confirmation of the receipt of training materials and guidelines from pharmacists and further confirmation of the receipt of training materials by the patient from pharmacists.

Another embodiment of the invention is a method of using rifaximin to treat a patient. An embodiment of the invention includes providing the patient with rifaximin and informing the patient or healthcare professional that the systemic exposure of rifaximin in the blood plasma is increased in patients suffering from liver failure, and that the administration of rifaximin to the patient with liver failure may affect the plasma concentration, safety or efficacy rifaximin.

Another embodiment of the invention includes a method of treating a subject suffering from a disease treatable with rifaximin. This method includes administering rifaximin to a subject and informing the subject that the systemic exposure of rifaximin in blood plasma is increased in subjects suffering from liver failure compared to subjects not suffering from liver failure.

Treatment methods

The methods provided herein are for determining a dose of rifaximin for treating, preventing, or partially relieving symptoms of intestinal disorders, in particular travelers diarrhea, in a subject further suffering from liver failure, for example, due to hepatic encephalopathy. Disorders related to bowel function include one or more of liver failure, cirrhosis, polycystic liver disease, irritable bowel syndrome, diarrhea associated with microorganisms, diarrhea associated with Clostridium difficile diarrhea, travelers diarrhea, excessive bacterial growth in the small intestine, Crohn's disease , chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy (or other diseases that lead to increased levels of ammonia) or pauchitis.

As used herein, the term “liver failure” includes diseases and disorders in which the subject has impaired functional activity of the liver. Clinically, subjects suffering from liver failure have reduced, for example, statistically significantly reduced, liver function. Hepatic failure usually leads to impaired liver function. An illustrative disease that serves as evidence of liver failure is hepatic encephalopathy.

As used herein, the term "hepatic encephalopathy" refers to a reversible neuropsychiatric disorder in the initiation of chronic or acute liver failure. When a liver is damaged in a subject, toxic substances that are normally metabolized in the liver accumulate in the blood, thereby impairing brain function. These toxic substances are, as a rule, nitrogen-containing substances, mainly ammonia. Having appeared in the brain tissue, the compounds cause changes in neurotransmission, which affect consciousness and behavior. There are 4 stages of a staged disorder associated with HE that are determined using the West Haven criterion (or Conn metric), starting from stage 0 (no detectable changes in the individual) and ending with stage 4 (coma, decerebral posture, dilated pupils). Typical symptoms of hepatic encephalopathy may include impaired cognitive activity, clapping tremors (asterixis), and decreased levels of consciousness, including coma (e.g., hepatic coma), cerebral edema, and, with some probability, death. Hepatic encephalopathy is commonly referred to in the literature as hepatic coma or portosystemic encephalopathy.

As used herein, the term “traveler’s diarrhea” refers to a gastrointestinal disease, usually among travelers. Most cases are caused by a bacterial, viral, or protozoal infection. The main source of infection is the absorption of food or water contaminated with feces. The duration of treatment for a particular bowel dysfunction will depend in part on this dysfunction. For example, HE can be treated every day for the remainder of a subject’s life, the duration of treatment for travelers diarrhea can be only 12 to about 72 hours, while the duration of treatment for Crohn’s disease can be about 2 days to 3 months. Dosages of rifaximin will also vary depending on the course of the disease.

The identification of those subjects who need preventive treatment of intestinal dysfunction is within the competence and knowledge of a specialist in this field of technology. Certain methods for identifying subjects at risk of developing bowel dysfunction, which can be treated in this way, are highly valued in the medical fields of technology, such as family history, travel history and proposed travel plans, the presence of risk factors associated with the development of this disease state in subject. A clinician specializing in the art can easily identify such applicants by using, for example, clinical trials, a physical examination, and a medical / family / travel history.

A method for assessing the degree of liver failure in a subject may include using any of the scoring systems presented above, such as the MELD index, the Child-Pugh index, the Conn indicator.

In yet another aspect, a method of treating a subject suffering or suffering from an intestinal disorder comprises administering to a subject in need of a therapeutically effective amount of rifaximin to treat, thereby, the subject. After identifying a subject suffering from or susceptible to intestinal upset, rifaximin is administered. Rifaximin can be administered, for example, after diagnosis, after an HE episode, during an HE episode, after a diagnosis of minimal HE is established, or when the critical flicker frequency reaches a level indicative of an HE episode, etc. As discussed herein, a physician may change the dosage of rifaximin administered to a subject to treat an intestinal disorder if the subject also suffers from liver failure. The effectiveness of treatment can be measured, for example, as a decrease in excess bacterial growth. Effectiveness can also be measured by alleviating the symptoms associated with an intestinal disorder, stabilizing the symptoms or stopping the symptoms associated with an intestinal disorder, for example, alleviating one or more of nausea, bloating, diarrhea, severity of a subsequent episode of HE, etc., or by increasing one or more time periods until the next episode of HE, cognitive ability, etc.

One embodiment of the invention is a method of treating or preventing hepatic encephalopathy (HE) by administering a therapeutically effective amount of rifaximin to a subject.

Embodiments of the invention relate to the discovery of the efficacy of rifaximin for the treatment and prevention of hepatic encephalopathy. Embodiments of the invention relate to the use of rifaximin to prevent the onset of symptoms of HE, as well as to lengthen the time to the first spontaneous episode of HE. In one embodiment, the time to the first spontaneous episode of HE was measured by increasing the Conn indicator to a degree of ≥2 (for example, from 0 or 1 to ≥2) or by increasing the Conn indicator and the degree of asterixis by one step each for those subjects an initial Conn score of 0. In another embodiment, the time to a spontaneous episode of HE was measured in time to any increase from the baseline of either the Conn indicator (mental state level) or the degree of asterixis using lower estimates of survival according to the method of Kaplan-Meyer cumulative proportions of subjects with any increase of 28, 56, 84, 112, 140 and 168 days.

Another embodiment of the invention was the average change from the initial level of the concentration of ammonia in the blood over time or the average change from the initial level of the values of the critical flicker frequency over time. An additional embodiment of the invention was expressed by the average daily consumption of lactulose in time dynamics, shifts from the initial level of Conn indicators in time dynamics; or shifts from the initial level of the degree of asterixis in time dynamics. Unless otherwise indicated, a shift in value is a change in this value from the original level.

Other measures of the effectiveness of the treatment methods described herein included the average change over time from the initial level of the chronic liver disease questionnaire score (CLDQ); average change from the initial level of the points of the Epworth drowsiness scale in time dynamics; and the proportion of subjects with an Epworth drowsiness score of> 10. Assessment of the severity of persistent hepatic encephalopathy may also be based, for example, on Conn scores.

In another embodiment, a subject suffering from, susceptible to, or in remission of hepatic encephalopathy (HE) can be given rifaximin for a period of about 24 weeks to 24 months. In the treatment of HE, rifaximin can be administered to the subject for 12 months or longer, for example, for the full life of the subject. In one embodiment, rifaximin is administered daily until the death of the subject.

In one embodiment, the invention relates to a method for reducing the risk of a spontaneous episode in a subject by administering rifaximin to the subject. In one embodiment, for subjects having a final HE episode 90 or more days before treatment, the risk of an adverse outcome was reduced by 58%. In another embodiment, the risk of an adverse outcome has been reduced by approximately 30-70%. In another embodiment, the risk has been reduced by about 40-70%.

In one embodiment, for subjects having a final HE episode more than 90 days prior to rifaximin administration, the risk of an adverse outcome was reduced by approximately 60%. In another embodiment, the risk of an adverse outcome has been reduced by approximately 2-80%.

In another embodiment, for subjects having two or more HE episodes 6 months before treatment, the risk of a spontaneous HE episode was reduced by approximately 56%. In one embodiment, the risk of a spontaneous episode of HE has been reduced by about 20-70%.

In another embodiment, for subjects having more than two episodes of HE six months before treatment, the risk of a spontaneous episode of HE was reduced by approximately 63%. In another embodiment, the risk has been reduced by about 30-80%.

As used herein, the term “terminal elimination rate constant” refers to a first-order rate constant describing the elimination of rifaximin from the body of a subject. This is the total elimination rate constant that describes the removal of rifaximin by all elimination processes, including excretion and metabolism.

As used herein, the term “plasma concentration” refers to the concentration of rifaximin in the blood plasma of a subject. Plasma rifaximin concentrations can be determined, for example, using reverse phase high performance liquid chromatography with tandem quadrupole mass spectrometry (LC / MS / MS), as described in the examples. The maximum concentration in plasma in equilibrium is indicated herein as Cmax, and the minimum concentration in plasma is indicated in this document as Cmin.

Used in this document, the term "clearance rate" refers to the volume of biological fluid completely purified from the metabolites of the drug, which is measured per unit time. Elimination occurs as a result of metabolic processes in the kidneys, liver, saliva, sweat, intestines, heart, brain and other places.

As used herein, alanine aminotransferase, also referred to as ALT, refers to a test performed to detect liver damage or liver failure. The level of this enzyme, ALT, is measured to determine if an individual has liver damage or disease. Low ALT levels are normally found in the blood. But with liver damage or disease, ALT is released into the bloodstream. ALT levels can be measured by methods known to those skilled in the art.

Pharmaceuticals

Embodiments of the invention also provide pharmaceutical compositions comprising an effective amount of rifaximin described herein and a pharmaceutically acceptable carrier. In a further embodiment, an effective amount is effective in treating a bacterial infection, for example, excessive bacterial growth in the small intestine, Crohn's disease, hepatic encephalopathy associated with antibiotic colitis and / or diverticulosis in a subject further suffering from liver failure.

For examples of the use of rifaximin to treat travelers diarrhea, see

each of which is incorporated herein by reference in its entirety. Embodiments of the invention also provide pharmaceutical compositions comprising rifaximin and a pharmaceutically acceptable carrier. Doses can be selected, for example, based on the required values of systemic absorption, elimination rate, plasma concentration, etc. Embodiments of the pharmaceutical composition further include excipients, for example, one or more diluents, binders, lubricants, substances to improve the disintegration of dosage forms, coloring agents, flavors or sweeteners. One composition may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar coated pills, lozenges, wafers, pellets and powders in a sealed package. For example, compositions can be formulated for topical use, for example, ointments, lipsticks, creams, gels and lotions. In an embodiment of the invention, rifaximin is administered to a subject using a pharmaceutically acceptable dosage form, for example, a pharmaceutically acceptable dosage form that provides continuous delivery of rifaximin to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the administration of a pharmaceutically acceptable dosage form to a subject.

In certain embodiments of the invention, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments of the invention described in detail below, the pharmaceutical compositions provided herein can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, jelly (water and non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection in the form of, for example, a sterile solution or suspension; (3) topical application, for example, in the form of a cream, ointment or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, in the form of a pessary, cream or foam; or (5) an aerosol, for example, in the form of an aqueous aerosol, liposome preparation, or solid particles containing a drug.

The phrase “pharmaceutically acceptable” refers to rifaximin compositions containing rifaximin and / or dosage forms which, through a thorough medical clinical evaluation, are suitable for use in contact with human and animal tissues without excess toxicity, irritation, allergic reaction, or other problems, or complications, commensurate with a reasonable ratio of benefit / risk.

The phrase “pharmaceutically acceptable carrier” includes a pharmaceutically acceptable substance, composition or excipient, for example, a liquid or solid excipient, diluent, excipient, solvent or encapsulating substance involved in the transfer or transport of the test chemical from one organ or part of the body to another organ or body parts. Each carrier is preferably “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not causing harm to the subject. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragant; (5) rye malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and a suppository with wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical dosage forms.

In solid dosage forms of rifaximin for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is usually mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or with any from the following: (1) fillers or dry diluents, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum; (3) humectants, such as glycerin; (4) substances that improve the disintegration of dosage forms, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) solution inhibitors, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared using a binder (e.g. gelatin or hydroxypropyl methyl cellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or a cross-linked sodium salt of carboxymethyl cellulose), a surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills, and granules, may optionally be at risk or may be prepared with coatings and coatings, such as enteric coatings and other coatings well known in pharmaceutical prescription manufacturing . They can also be formulated to provide sustained or controlled release of the active ingredient using, for example, hydroxypropyl methylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through bacteria-retaining filters or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain contrast agents and may be in the composition that they release the active ingredient (s) only, or preferably, in a certain part of the gastrointestinal tract, in some cases, in a prolonged manner. Examples of casting compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if necessary, with one or more of the excipients described above.

Liquid dosage forms for the oral administration of rifaximin include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular cottonseed, peanut, corn oil, seed germ oil, olive, castor and sesame oil), glycerin, tetrahydrofuryl Hydroxy alcohol, polyethylene glycols and esters of sorbitan fatty acids and mixtures thereof.

In addition to inert diluents, compositions for oral use may include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, coloring agents, perfumes and preservatives.

Suspensions, in addition to rifaximin, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth and mixtures thereof.

Pharmaceutical compositions for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing rifaximin with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository with wax or salicylate, and which are solids at room temperature, but liquid at body temperature and thus will melt in the rectum or vagina and release active substance.

Compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers that are known as suitable means in the art.

Dosage forms for topical or transdermal administration of rifaximin include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalers. Rifaximin can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be needed.

Ointments, pastes, creams and gels may contain, in addition to rifaximin, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to rifaximin, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays may additionally contain standard propellants such as chlorofluorocarbons and volatile non-substituted hydrocarbons such as butane and propane.

Rifaximin may alternatively be administered as an aerosol. This is done by preparing an aqueous aerosol, liposome preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension may be used. Sound sprays are preferred because they minimize the effects of shear agents, which can lead to decomposition of the compound.

Injectable depot forms are made by forming microencapsulated rifaximin matrices in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot dosage forms are also prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissue.

When rifaximin is administered as a pharmaceutical preparation to humans and animals, it can be administered in pure form or as a pharmaceutical composition containing, for example, from 0.1 to 99.5% (more preferably from 0.5 to 90%) active ingredient in combination with a pharmaceutically acceptable carrier.

Regardless of the route of administration, the selected rifaximin that can be used in the pharmaceutical compositions provided herein is formulated into pharmaceutically acceptable dosage forms by methods known to those skilled in the art.

Actual dosage levels and dynamics of administration of the active ingredients in the pharmaceutical compositions may vary so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition and route of administration without being toxic to the subject. A typical dose range is from 25 to 3000 mg per day.

The preferred dose of rifaximin is the maximum that a subject can tolerate without the development of serious side effects. Preferably, rifaximin is administered at a concentration of from about 1 mg to about 200 mg per kilogram of body weight, from about 10 to about 100 mg / kg, or from about 40 mg to about 80 mg / kg of body weight. Ranges that are intermediate to the above values are also intended to be part of the invention.

In illustrative embodiments, rifaximin is administered to subjects 1, 2, 3, or 4 times a day. Typical dosages include oral doses of 100, 200, 300, 400, 500, 550, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mg rifaximin. Ranges that are intermediate to the above values are also intended to be part of the invention. In a particular illustrative embodiment, 600 mg of rifaximin per day is administered to subjects. In a further particular embodiment, three 200 mg tablets per day are administered to subjects.

In a combination therapeutic treatment, rifaximin and another drug (a) are administered to mammals (e.g., humans, male or female) by conventional methods. Medicines may be administered in unit dosage form or in unit dosage form. Effective amounts of other therapeutic agents are well known to those skilled in the art. However, the competence of a person skilled in the art is to determine other optimal effective quantitative ranges of the therapeutic agent. In one embodiment of the invention, in which another therapeutic agent is administered to an animal, an effective amount of rifaximin is less than its effective amount if another therapeutic agent is not administered. In another embodiment, an effective amount of a conventional agent is less than its effective amount if rifaximin is not administered. Thus, unwanted side effects associated with high doses of any agent can be minimized. Other potential benefits (including, without limitation, an improved dosage regimen and / or reduced drug cost) are apparent to those skilled in the art.

In various embodiments, methods of treatment (e.g., prophylactic or therapeutic agents) are administered at intervals of less than 5 minutes, less than 30 minutes, at intervals of 1 hour, at intervals of about 1 hour, at intervals of about 1 hour to about 2 hours, from about 2 hours to about 3 hours, from about 3 hours to about 4 hours, from about 4 hours to about 5 hours, from about 5 hours to about but 6 hours, with an interval of about 6 hours to about 7 hours, with an interval of about 7 hours to about 8 hours, with an interval of about 8 hours to about 9 hours, with an interval of about 9 hours to about 10 hours, with an interval from about 10 hours to about 11 hours, with an interval of about 11 hours to about 12 hours, with an interval of about 12 hours to about 18 hours, with an interval of 18 hours to 24 hours, with an interval of 24 hours to 36 hours, s interval scrap from 36 hours to 48 hours, with an interval from 48 hours to 52 hours, with an interval from 52 hours to 60 hours, with an interval from 60 hours to 72 hours, with an interval from 72 hours to 84 hours, with an interval from 84 hours to 96 hours, or at intervals of 96 hours to 120 hours. In a preferred embodiment of the invention, two or more treatments may be prescribed within the same subject visit.

In certain embodiments, one or more compounds and one or more other methods of treatment (e.g., prophylactic or therapeutic agents) are administered cyclically. Cyclically repeated therapy includes the appointment of a first treatment method (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by a second treatment method (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally followed by a third treatment method (e.g. prophylactic or therapeutic agent) for a period of time and so on, and the repetition of this sequential appointment, for example, a cycle to reduce the development tions of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies, and / or to improve effectiveness of treatments.

In certain embodiments of the invention, the administration of the same compounds can be repeated, and the administration can be separated from each other by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months. In other embodiments, the administration of the same treatment method (eg, prophylactic or therapeutic agent) other than rifaximin may be repeated, and the administration may be separated from each other for at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.

According to certain indications, a longer treatment time may be required. For example, treatment of travelers' diarrhea can last from about 12 hours to about 72 hours, while treatment of Crohn's disease can last from about 1 day to about 3 months. Treatment for hepatic encephalopathy may continue, for example, throughout the remainder of the subject's life. IBS treatment may be intermittent for weeks or months at a time or for the remainder of the subject's life.

Product

Another embodiment of the invention includes articles that include, for example, a container containing a pharmaceutical composition suitable for oral or topical administration of rifaximin, in combination with printed instructions for use, providing information about when a particular dosage form should be administered with food and when it should be taken on an empty stomach. The recommended dose may be changed for administration to a subject suffering from liver failure, or may include instructions for administering to a subject suffering from liver failure. Typical dosage forms and administration protocols are described below. The composition is contained in any suitable container capable of storing and dispensing the dosage form and which does not substantially interact with the composition and is additionally in physical contact with the appropriate labeling. Instructions for use are in accordance with the methods of treatment, as described above in this document. Labeling may be associated with the container by any means that maintain their physical contact, by way of unlimited example, they may be in packaging material, such as a box or shrink plastic film, or may be associated with instructions related to the container, for example using glue that does not complicate understanding of instructions for use or other stickers or storage media.

Another aspect is an article of manufacture that includes a container containing a pharmaceutical composition comprising rifaximin, wherein the container preferably contains a rifaximin composition in unit dosage form and is associated with printed instructions for use informing of different absorption when the pharmaceutical composition is administered with or without food.

In another aspect, provided herein are an article or kit comprising rifaximin or a pharmaceutical composition thereof, packaged with instructions for administration to subjects having liver failure. In one embodiment of the invention, the instructions inform the prescribing physician, pharmacist, or subject that subjects having hepatic encephalopathy systemically absorb more rifaximin than subjects with normal, for example, fully functional, liver systems. In one embodiment of the invention, the instructions inform prescribing physicians that they must determine if the subject had liver failure before rifaximin was administered to the subject for treating bowel disease. In one embodiment of the invention, the instructions inform prescribing physicians that they must consider the dosage or dosage regimen when administering rifaximin to a subject having hepatic encephalopathy. Additionally, the instructions may provide guidance on the use of the drug for subjects with liver failure. In another embodiment of the invention, the instructions inform the subject and / or healthcare provider that there is a difference in the effects of rifaximin in blood plasma between subjects with HE and subjects with normal liver function.

Packed compositions are also contemplated and may include a therapeutically effective amount of rifaximin. Rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat a subject suffering or suffering from an intestinal disorder and is packaged with instructions for treating a subject suffering or susceptible to an intestinal disorder.

Kits are also provided herein, for example, kits for treating an intestinal disorder in a subject. The kits may contain, for example, rifaximin and instructions for use in treating a subject with an intestinal disorder who also suffers from liver failure. Instructions for use may contain instructions for use, information on dosing, information on storage, etc.

Packed compositions are also contemplated and may include a therapeutically effective amount of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat a subject suffering or suffering from an intestinal disorder and is packaged with treatment instructions for a subject suffering or suffering from an intestinal disorder.

EXAMPLES

Embodiments of the invention are based in part on the demonstration that rifaximin is differentially absorbed in subjects having other clinical conditions, for example, hepatic encephalopathy. It should be appreciated that the invention should not be construed as being limited by the examples described below; on the contrary, the invention should be considered to include any and all applications provided for in this document, and all equivalent options within the scope of qualification of an ordinary specialist.

Example 1

A clinical study of the administration of rifaximin to subjects with impaired liver function

To determine the effect of impaired liver function on the effectiveness of rifaximin, studies have been conducted in subjects with hepatic encephalopathy (HE). HE, also known as hepatic coma or portosystemic encephalopathy, is a serious, rare, complex, potentially reversible, neuropsychiatric syndrome associated with progressive liver disease. Nitrogen-containing substances, primarily ammonia, gain access to systemic circulation due to decreased liver function or portosystemic anastomoses. Once in the brain tissue, these compounds cause changes in neurotransmission, which affects consciousness and behavior. There are 4 progressive stages of the lesion associated with HE, which are determined using the West Haven criterion (or Conn indicator), starting from stage 0 (no detectable changes in the individual) and ending with stage 4 (coma, decerebral posture, dilated pupils).

Treatment of patients with chronic HE includes: 1) providing symptomatic therapy, 2) identifying and eliminating provoking factors, 3) reducing the nitrogen-containing load from the intestine, and 4) assessing the need for long-term therapy. Nitrogen-containing load from the intestine, as a rule, reduce the use of non-absorbable disaccharide (lactulose) and / or antibiotics. Although lactulose is considered the primary treatment in the United States, it has not yet been approved for use in either treatment or prevention of HE. Rifaximin is a promising therapy for treating patients with HE due to its demonstrated effectiveness and due to deficiencies of systemic antibiotics and nonabsorbable disaccharides. The disadvantages of chronic systemic antibiotic therapy include nephrotoxicity and ototoxicity, and the disadvantages of lactulose therapy include dehydration due to diarrhea (provoking factor HE), an overly sweet taste, and side effects from the gastrointestinal tract.

In this example, rifaximin was given on an outpatient basis at a dosage of 550 mg twice daily (total daily dose was 1100 mg of rifaximin). Subjects were given a dose of 550 mg of rifaximin twice a day for at least 7 consecutive days prior to the day the samples were taken for pharmacokinetic studies.

To ensure equilibrium plasma concentrations, blood samples were taken for pharmacokinetic analysis at least 7 consecutive days of a 550 mg dose of rifaximin twice daily. Blood samples for pharmacokinetic analysis were collected on one day, after at least 7 consecutive days of 100% compliance with the dosage regimen of rifaximin in an amount of 550 mg twice a day. Serial samples for pharmacokinetic analysis were collected within 12 hours (for example, before dosing and 1, 2, 4, 6, 8, 10, and 12 hours after dosing) to give a steady-state profile of the plasma rifaximin concentration profile in time. Subjects starved overnight (no meal for approximately 10 hours) prior to rifaximin administration and were given standard light meals 1 hour after administration of the study drug (after the planned 1-hour blood plasma intake).

The pharmacokinetic parameters of rifaximin in blood plasma were calculated using non-compartmental methods (for example, the standard extra-model approach).

A sample was taken for pharmacokinetic analysis on the same day, at least 7 consecutive days, at 100% compliance with the dosage regimen of rifaximin in an amount of 550 mg twice a day. A total of 8 blood samples were collected within 12 hours (for example, before the dose and 1, 2, 4, 6, 8, 10, and 12 hours after the dose) to give an individual profile of plasma rifaximin concentration profile blood over time over a 12-hour dosing interval.

Plasma rifaximin concentrations were determined by reverse phase high performance liquid chromatography with tandem quadrupole mass spectrometry (LC / MS / MS) using a reliable analytical method. The lower limit of quantitation (LOQ), the deviation of calibration standards from theoretical values and accuracy were established using standard methods.

The pharmacokinetic parameters of rifaximin in blood plasma were calculated using WinNonlin® Enterprise (version 5.2).

Pharmacokinetic parameters were calculated using non-compartmental methods (e.g., standard extra-model approach). The following equilibrium pharmacokinetic parameters of rifaximin in blood plasma were calculated using the actual concentration profiles over time for each subject:

Parameter Definition AUC _τ The area under the concentration versus time curve, starting from time 0 (before dose) during the 12-hour tau (τ) dosing interval, is calculated using the linear trapezoidal formula (also denoted AUC _0-12 ). C _max The maximum concentration in plasma at equilibrium. Also referred to as Cmax _ss . C _min Minimum plasma concentration at equilibrium. Also denoted by Cmin _ss . T _max Time to reach maximum plasma concentration at equilibrium. Also referred to as Tmax _ss .

Other parameters, such as the apparent total clearance (CL / F) and the final half-life or half-life (t _1/2 ), were determined if relevant data were available. In addition to the planned analysis, AUC from time 0 (before dose) to the last measured concentration (AUC _0-τ ) was also calculated.

The individual plasma concentrations and pharmacokinetic parameters of rifaximin were summarized for the total pharmacokinetic population and the severity of liver failure using Child-Pugh indicators (A and B) using descriptive statistics (e.g. N, average, SD, CV%, median, minimum , maximum, geometric mean).

Demographic and other basic characteristics were summarized for subjects according to the severity of liver failure using Child-Pugh indicators (A and B) and the terminal stage model model of liver disease (MELD) using descriptive statistics. Key features included albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), serum creatinine and serum total bilirubin, where the baseline was determined as the last available measurement before the first dose of rifaximin.

The pharmacokinetic parameters of rifaximin AUC _τ and C _max in subjects with indicators of Child-Pugh A and B (for example, mild and moderate forms of liver failure) were compared using an analysis of variance model (ANOVA).

Paired ANOVA was used to evaluate rifaximin concentrations measured prior to dosing and 12 hours after dosing to assess possible differences in equilibrium rifaximin concentrations.

A total of 25 subjects were included in the population according to pharmacokinetic parameters and were tested for the safety of drug administration.

Initially, eighteen (18) of 25 subjects (72.0%) had mild liver failure (e.g., Child-Pugh score A). The remaining 7 subjects (28.0%) initially had a moderate form of liver failure (for example, Child-Pugh score B).

The pharmacokinetic parameters of rifaximin were compared with the results of a separate study in healthy subjects with normal liver function.

Demographic and main characteristics of the subjects

Table 1 summarizes the demographic characteristics for all subjects included in the study. A total of 25 subjects were included in the study; 17 subjects (68.0%) were males and 8 subjects (32.0%) were females. The average age among subjects participating in the study was 58 years old (range from 45 to 68 years). Twenty-two subjects (88.0%) were white and the remaining 3 subjects (12.0%) were black. Seven out of 25 subjects (28.0%) belonged to the Hispanic ethnic group.

Eighteen (18) subjects had a Child-Pugh score A, and seven subjects had a Child-Pugh score B. Fifteen (15) subjects had a baseline MELD index of <11, and 10 subjects had a baseline MELD of 11 to 18 (inclusive). Most subjects participating in the study initially had a Conn score of 0 (22/25; 88.0%) for the pharmacokinetic sub-study; 3 out of 25 subjects (12.0%) initially had a Conn score of 1.

Table 1
Demographic and basic characteristics of the subjects - all subjects included in the study Characteristic N = 25 N 25 Average age (± SD), years 58 (± 5.34) Gender: n (%) Men 17 (68.0) Women 8 (32.0) Race: n (%) White-skinned 22 (88.0) Blacks or African Americans 3 (12.0) Child-Pugh Ratio: n (%) A 18 (72.0) B 7 (28.0) MELD Index: n (%) <11 15 (60.0) 11-18 10 (40.0) Conn indicator Degree 0 22 (88.0) Degree 1 3 (12.0) Abbreviation: MELD = end-stage model of liver disease.

In general, demographic characteristics were comparable for subjects with Child-Pugh A and B. The main demographic characteristics were also mostly similar for subjects that had an initial MELD index <11, and subjects that had an initial MELD index ranging from 11 to 18 (inclusive). A higher proportion of subjects with a MELD index in the range of 11 to 18 were Hispanic subjects (50.0% versus 13.3%) compared with subjects with a MELD index of ≤10.

Basic laboratory data corresponded to impaired liver function among subjects. The results of major liver function tests indicated greater liver failure among subjects belonging to the Child-Pugh B category, compared with subjects belonging to the Child-Pugh A category, and greater liver failure among subjects with an MELD index ranging from 11 to 18 compared with subjects with a MELD index <11. In particular, subjects of the Child-Pugh B category and subjects with an MELD index of 11-18 initially had significantly higher baseline values for alkaline phosphatase, AST, and direct and total bilirubin.

On the day preceding the collection of pharmacokinetic data, most subjects received their 2 doses of rifaximin at intervals of approximately 12 hours. The shortest dose interval for any subject was 10 hours; the longest interval for any subject was 13.55 hours. The second dose of rifaximin was administered without dinner, either before meals (13 subjects) or after meals (12 subjects).

On the day of sampling for pharmacokinetic analysis, the morning dose of rifaximin was administered after at least 10 hours of overnight fasting. All subjects were given light food 1 hour after dosing, following a 1-hour time point for taking a blood plasma sample for pharmacokinetic analysis. The next dose of rifaximin was introduced immediately after the 12-hour time point for taking a blood plasma sample for pharmacokinetic analysis, with 1 exception.

Average plasma rifaximin concentrations reached a maximum level 1 hour after drug administration and then slowly dropped over 12 hours (Fig. 1). Plasma rifaximin concentrations were above the lower limit of quantitation (LOQ) over the entire 12-hour sampling interval of all subjects. A total of 5 subjects showed bumpy plasma concentration profiles.

Pharmacokinetic parameters of rifaximin in equilibrium in subjects with liver failure classified as Child-Pugh A and Child-Pugh B

Table 2 summarizes the pharmacokinetic parameters of rifaximin after at least 7 days of treatment of subjects with insufficient liver function according to Child-Pugh and for the entire pharmacokinetic population. A column containing values determined for healthy subjects in a separate study is presented to facilitate comparison.

Comparative analysis among subjects with Child-Pugh A (mild insufficiency) versus Child-Pugh B (mild insufficiency) and among subjects with an MELD index <11 (mild insufficiency) versus 11 to 18 (moderate form) failure)

The average values of AUC _τ and C _max in subjects with a Child-Pugh B index (161 ng * h / ml and 25.1 ng / ml, respectively) were approximately 36% and 29% higher than those observed in subjects with a Child- Pugh A (118 ng * h / ml and 19.5 ng / ml, respectively). The rifaximin elimination rate in subjects with a Child-Pugh B score was 29% longer than that observed in subjects with a Child-Pugh B score (10.5 hours compared to 8.12 hours). The pharmacokinetic parameters of rifaximin were characterized by a coefficient of variability between subjects (CV%) for AUC _τ and C _max lying in the range from about 50 to 60%. This was in accordance with the variability previously observed in healthy subjects, for example, CV% from 45% to 60%.

The pharmacokinetic parameters of rifaximin AUC _τ and C _max in subjects with indicators of Child-Pugh A and B (mild and moderate forms of liver failure, respectively) were compared using the ANOVA model. In cases where it was not possible to calculate AUC _τ , the corresponding AUC _0-τ values were used for output statistics.

The results of one-way ANOVA analysis of variance are summarized in Table 3. The ratio of geometric LSM AUC _τ for Child-Pugh B to that for Child-Pugh A was 151.2% with 90% confidence intervals from 98.8% to 231.5% ( p = 0.1092). The ratio of geometric LSM C _max for Child-Pugh B to that for Child-Pugh A was 149.9% with 90% confidence intervals from 98.8% to 227.5% (p = 0.1096). Confidence intervals for LSM ratios were very large, taking into account the variability between subjects in terms of AUC _τ and C _max in both populations.

Covariance analysis showed that biochemical markers of insufficient liver function, for example, increased albumin, total bilirubin, and the values of the international normalized ratio correlated with increased systemic exposure to rifaximin (AUC _tau and C _max ) and reduced clearance when taken orally (CL / F).

The pharmacokinetics of rifaximin was evaluated in subjects with insufficient liver function. After observing the same dosing schedule (for example, 550 mg twice a day), the values of the systemic exposure to rifaximin (AUC _tau ) at equilibrium in subjects with Child-Pugh A and B were approximately 9.6 and 13.1 times higher , respectively, those observed in healthy subjects at equilibrium.

Systemic exposure was compared using a specific method for evaluating liver function, the MELD index. The ratios of geometric LSM and 90% CIs for AUC _τ and C _max were determined for subjects with an MELD index <11 (n = 15) compared to the MELD index in the range from 11 to 18 (n = 10). The results of this analysis (see table 4) showed that systemic exposure was statistically significantly higher (p <0.05) in subjects with moderate hepatic impairment when compared with mild hepatic impairment when the MELD index was used to evaluate liver function. The ratio AUC _τ for the MELD index <11 in comparison with the index from 11 to 18 was 168.22% with 90% CIs equal to from 110.5% to 256.2% (p = 0.0451); and the C _max ratio was 178.12% with 90% CIs equal to 116.7% to 271.8% (p = 0.0283). The correlation between the MELD index and the Child-Pugh category in 25 subjects participating in the sub-study was weak (correlation coefficient: p = 0.399).

Rapid absorption of rifaximin with a maximum concentration in blood plasma occurred 1 hour after the dose in the vast majority of subjects. A total of 3 subjects in the Child-Pugh A group had delayed absorption of rifaximin with a maximum plasma concentration observed in the range from 6 to 10 hours after dosing.

Comparison with subjects with normal liver function

The results of the current study were compared with archival data for subjects with normal liver function. The arithmetic mean (± SD) of the pharmacokinetic parameters of repeated administration of 550 mg of rifaximin twice a day in healthy subjects is presented in table 5.

Rifaximin exposure values (AUC _τ ) in subjects with Child-Pugh A and B (118 and 161 ng * h / ml, respectively) were approximately 9.6 and 13.1 times higher than those observed in healthy subjects after oral administration doses of 550 mg twice daily (12.3 ng * h / ml), respectively. With the exception of t _{1/2, the} interindividual variability of the pharmacokinetics of healthy subjects was basically similar to that measured in subjects with liver failure.

Comparison of concentrations before dosing with a 12-hour time point after dosing on the day of the pharmacokinetic sub-study

The results of paired ANOVA for evaluating drug concentrations before dosing at 0- and 12-hour time points are presented in Table 6.

These results indicate that the rifaximin concentration at the 12-hour time point after drug administration was reduced by 37.8% when compared with the morning concentration before drug administration (p <0.0001). It was shown that the introduction of the drug along with food increased the degree of absorption of rifaximin by approximately 2-3 times. The morning dose was administered on an empty stomach.

Covariance analysis

A multi-parameter linear regression model was developed to evaluate the effect of various covariates on AUC _τ , C _max and CL / F of rifaximin. The following covariates were investigated in the model: Child-Pugh score and laboratory test results (albumin, alkaline phosphatase, ALT, AST, creatinine clearance, serum creatinine, INR and total bilirubin). Covariates selected for analysis are known indicators of liver and kidney function. A visual assessment was performed to determine the potential trend between the analyzed covariates and AUC _τ , C _max and CL / F.

The results are presented below in tables 7-9.

Covariance analysis showed that biochemical markers of insufficient liver function, for example, elevated albumin, total bilirubin and INR, correlated with increased systemic exposure to rifaximin (AUC _τ and C _max ) and decreased oral clearance (CL / F) in this study .

The model with the highest R ² included albumin, total bilirubin, INR and ALT (R ² = 53.6%, Cp = 4.4101).

Based on the results of the analysis of the models, it was decided that a simple model includes only albumin, total bilirubin and INR. The final model for AUC _τ is presented in table 7.

The 3-parameter model with the highest R ² included total bilirubin, INR and ALT (R ² = 39.1%, Cp = 3.7193). Within a subset of models with 4 parameters, the model with the highest R ² included albumin, total bilirubin, INR and ALT (R ² = 46.9%, Cp = 3.0598). Given that R ² was higher for a 4-parameter model, it was decided that a simple model included 4 parameters: albumin, total bilirubin, INR and ALT. The final model is presented in table 8.

Within a subset of models with 4 parameters, the model with the highest R ² included albumin, total bilirubin, INR and ALT (R ² = 54.9%, Cp = 3.4103). The results of this model are presented in table 9.

EXAMPLE 2

A randomized, double-blind, dose-finding study to evaluate the efficacy, tolerability, and safety of rifaximin in patients with grade I, II, or III hepatic encephalopathy.

A pharmacokinetic analysis was performed in subjects with HE in a dose selection study of the drug. A total of 54 subjects (32 men, 22 women, aged 32 to 82 years) were included in the study and they took 200, 400 or 800 mg of rifaximin three times a day (200 mg tablets), which corresponded to daily doses equal to 600, 1200 and 2400 mg, respectively, for 7 consecutive days. Plasma and urinary rifaximin concentrations were measured by the LC-MS / MS method (LLOQ = 0.5 ng / ml).

The excretion of rifaximin with urine is presented in table 10.

There was no relationship between the administered dose and the amount of rifaximin excreted in the urine. At the 24-hour time point for urine sampling after the last (third) dose of 200, 400 and 800 mg, on the last day of the drug administration, day 7, the average (SD) amount of rifaximin excreted in the urine was in the range from 0, 06% (± 0.66%) to 0.1% (0.093%) of the dose, and these values are consistent with rifaximin isolated (for example, 0.030% ± 0.020% of the dose) after a single administration of a radiolabeled dose of 400 mg .

The average maximum plasma rifaximin concentrations of 2.7, 10.5 and 13.5 ng / ml were measured 3 hours after the first single dose of 200, 400 and 800 mg, respectively.

EXAMPLE 3

Rifaximin absorption

The study was performed on subjects with liver failure. The average values of AUC _tau and C _max in subjects with a Child-Pugh B index (161 ng · h / ml and 25.1 ng / ml, respectively) were approximately 36% and 29% higher than those observed in subjects with a Child- Pugh A (118 ng · h / ml and 19.5 ng / ml, respectively). The half-life t _{1/2 of} rifaximin in subjects with a Child-Pugh B score was approximately 29% longer than that observed in subjects with a Child-Pugh B score (10.5 hours versus 8.12 hours). The pharmacokinetic parameters of rifaximin had a percentage of the interindividual coefficient of variability (CV%) for AUC _0-tau and C _max in the range from about 50% to 60% in both subpopulations. This is consistent with the variability previously detected in healthy subjects, for example, CV% from 45% to 60%.

Rifaximin was rapidly absorbed with a maximum concentration in the blood plasma, detected 1 hour after the dose, in the vast majority of subjects. A total of 3 subjects in the Child-Pugh A group had delayed absorption of rifaximin with a maximum plasma concentration detected in the range from 6 to 10 hours after dosing. In some subjects, flat or bumpy plasma rifaximin concentration profiles were detected. Abnormalities in the motor activity of the gastrointestinal tract and bile secretion in subjects with cirrhosis and HE could potentially explain the delayed / prolonged absorption of rifaximin found in this study.

The results of multiple linear regression models showed that biochemical markers of hepatic function, for example, increased albumin, total bilirubin, and the international normalized ratio, correlated with increased systemic exposure to rifaximin (AUC _tau and C _max ) and decreased oral clearance (CL / F). A positive correlation was also found between the initial level of alanine aminotransferase and C _max .

In a separate study, pharmacokinetic parameters were investigated. This population included 18 subjects (72%) with mild liver failure (Child-Pugh A) and 7 subjects with mild liver failure (Child-Pugh B). A study of healthy subjects included 28 subjects.

The values of rifaximin exposure (AUC _tau ) in subjects with Child-Pugh A and B (118 and 161 ng · h / ml, respectively) were approximately 9.6 and 13.1 times higher, respectively, of those found in healthy subjects after taking an oral dose of 550 mg twice daily (12.3 ng · h / ml). With the exception of t _1/2 , the interindividual pharmacokinetic variability in healthy subjects was generally similar to that measured in subjects with liver failure.

Example 4

3 phase research

A randomized, double-blind, placebo-controlled, complex phase 3 study (Study A) was conducted to evaluate the efficacy and safety of rifaximin in patients at the time of the study in remission of a previously detected HE. The study consisted of a screening period (4 days), a follow-up period (3 days), a baseline visit and a treatment period (6 months). After determining suitability, patients went through a baseline assessment period before randomization. This period lasted 7 days and was used to determine the suitability of patients, provide adequate instructions for the treatment providers, and establish the initial mental status and neuromuscular function before entering the double-blind period. Patients were randomized to receive a 550 mg twice daily rifaximin tablet or a placebo twice daily tablet for 6 months. Subjects were able to use lactulose as concomitant drug therapy, and 91% of subjects in both groups took lactulose during the study. Subjects underwent a thorough assessment of mental status (Conn indicator) and neuromuscular function (degree of asterixis) to determine the occurrence of a spontaneous episode of HE by researchers and staff at each personal research visit, from telephone conversations, reports of carers, and from subject diaries . Subjects were excluded from the study during a spontaneous marked episode of HE. After participating in the study, subjects had the opportunity to be included in an open, extended clinical study (Study B).

Dose of rifaximin

The dosage regimen used (550 mg twice daily) in Study A was based on past clinical experience with rifaximin in patients with HE and other subject populations. In a number of previous studies, rifaximin was safe and effective in subjects with HE at a dose of 1200 mg per day (2 × 200 mg tablets three times a day) with or without concomitant therapy with lactulose. In a 6-month study of rifaximin compared with neomycin, 1200 mg / day of rifaximin and neomycin (3 g / day) had comparable efficacy in patients with HE. In a 3-month study of rifaximin compared with lactitol, subjects who received 1200 mg / day of rifaximin (2 × 200 mg tablets three times a day) showed significant improvements in the end-points of HE.

In the study, in order to determine the optimal dose of the drug for subjects with severe HE symptoms, there was a dose-dependent tendency for the PSE index to improve up to 1200 mg (2 × 200 mg tablets three times a day). Similar results were obtained for doses of 1200 mg and 2400 mg (4 × 200 mg tablets three times a day) (table 11). In the analysis of the dose-dependent effect, the Jonkhier-Terpstra criterion indicated a tendency toward an improvement in the PSE index for a combination of dose groups (p = 0.0586).

Table 11
Change in PSE index (ITT population) relative to baseline PSE ^a Index Study C (N = 54) Rifaximin 600 mg / day
N = 18 1200 mg / day
N = 18 2400 mg / day
N = 18 At the end of treatment (day 7) minus baseline n fourteen 16 16 Mean value (standard deviation) -0.064
(0,137) -0.103
(0,137) -0.107
(0,149) Abbreviation: PSE: portal systemic encephalopathy; EEG: electroencephalogram.
and the PSE index was calculated as follows: [Mental state (Conn indicator) × 3 + degree of asterixis × 1 + degree of NCT × 1 + estimate of ammonia content × 1 + estimate of EEG × 1 (if available) / 24 (or 28 if EEG data is available]]. (24 [or 28 if EEG results are included] is the highest possible score, and higher scores indicate more severe symptoms of HE.

Study population

For Study A, male or female subjects 18 years of age or older were eligible for study if they met the following criteria:

- Index Conn 0 or 1

- A case history of 6 months with ≥2 episodes of severe HE associated with chronic liver disease (e.g., cirrhosis or portal hypertension) with documented disease severity equivalent to Conn ≥2 before screening (i.e., subjects had documented, recurring, expressed HE). At least 1 previous episode has been verified by medical records. Episodes of hepatic encephalopathy, mainly attributed to GI bleeding, drugs (e.g. narcotic drugs, tranquilizers, sedatives), renal failure requiring dialysis, or CNS stroke, such as subdural hematoma, were not considered as previous, genuine HE episodes.

- Index MELD≤25,

- Distribution of TIPS or changes> 3 months prior to screening (if available) and

- Had a friendly family or other staff who continued to be supervised and accessible to the subject during the study.

Subjects were excluded from the study if the following criteria were met:

- Waiting for liver transplantation within 1 month of screening

- Alcohol consumption within 14 days of screening, sedatives for 7 days or confirmation of drug dependence

- HIV as determined by medical history

- Medical history of a TV infection or treatment of a TV infection

- Active SBP or daily prophylactic antibiotic therapy

- GI bleeding requiring hospitalization and blood transfusion ≤ months of screening

- The presence of intestinal obstruction or inflammatory bowel disease

- Renal failure (serum Cr> 2.0 mg / dL)

- Anemia (HgB <8 g / dl)

- Hypovolemia or abnormalities in the electrolyte content (Na + <125 meq / l, Ca ++> 10 mg / dl, K + <2.5 meq / l

- Prohibited concomitant drug therapy required

Determining the effectiveness of end indicators

The primary endpoint in Study A was the time to the first spontaneous, pronounced HE episode. A spontaneous pronounced episode of HE was defined as an increase in the Conn score to a degree of ≥2 (i.e. 0 or 1 to ≥2) or an increase in the degree of Conn or asterixis by 1 point for those subjects who were included in the study with a Conn score of 0 The time before a spontaneous marked episode of HE was the duration from the first administered dose of the investigational drug to the first spontaneous marked episode of HE.

Key supporting outcomes are listed below:

1. Time to first hospitalization associated with HE.

2. Time to any increase from the initial value of the degree of Conn (level of mental status).

3. Time to any increase from the initial value of the degree of asterixis.

4. The average value of the change from the initial level of the degree of manifestation of fatigue in CLDQ at the end of treatment.

5. The average value of the change from the initial level of concentration of ammonia in the venous blood at the end of treatment.

Detailed characteristics of the treatment group for Study A are presented below in tables 12-13.

Main characteristics

Key characteristics of hepatic encephalopathy in the ITT population, such as the severity of HE for recent episodes of severe HE (Conn scores and degrees of asterixis) and the time since the last HE episode, are summarized in Table 14. Liver disease characteristics and other baseline characteristics of subjects in the ITT population, such how the severity of the disease (MELD index), the time since the first diagnosis of progressive liver disease and the etiology of liver disease are summarized in tables 15, 16 and 17. The main characteristics are generally comparable waiting for treatment groups.

Study Design B

Study B is a continuous phase 3, multicenter, open, extended-treatment study evaluating the long-term safety of rifaximin at a dose of 550 mg twice daily in subjects with a history of recurrent, episodic, severe HE. All eligible subjects had a history of severe HE episodes with documented disease severity with Conn ≥2 for 12 months prior to screening, Conn ≤2 when enrolled, and either were participants in Study A or were new subjects. Treatment with rifaximin in the form of tablets of 550 mg twice a day was planned to be carried out for at least 24 months, or until the regulatory authority has authorized it. Concomitant therapy with lactulose is optional.

Although Study B was primarily intended to assess the long-term safety of 550 mg of rifaximin, additional evaluations of the effectiveness of Conn and the degree of asterixis were obtained during the study. In Study B, spontaneous, expressed HE was defined as an increase in Conn to a level of ≥2, an increase in Conn and asterixis of 1 level each for those subjects who started the study with a Conn of 0, and an increase in Conn to a ≥3 for subjects who at the very beginning of the study had a Conn score of 2.

Research Design C, D, and E

Study C was a double-blind study to determine the optimal dose in subjects with a degree of 1-3 HE included in the study at 5 centers in the United Kingdom. Subjects were randomized to receive rifaximin at a daily dose of 600 mg (200 mg three times a day), 1200 mg (400 mg three times a day) or 2400 mg (800 mg three times a day) for 7 days. The planned list of participants consisted of 54 subjects (18 in the group).

Study D was a double-blind, controlled with two placebo, comparative study of 3 phases of rifaximin in the amount of 1200 mg / day and lactitol in the amount of 60 g / day for a period of up to 10 days in the treatment of subjects with hyperammonemia and liver cirrhosis with a degree of 1-3 HE included in the study at 16 centers in Spain. The planned list of participants consisted of 120 subjects (60 in the group).

Study E was an international, multicenter, randomized, double-blind, placebo-controlled, parallel-phase, 3-phase study comparing 400 mg of rifaximin three times a day with placebo in subjects with cirrhosis of the liver having hepatic encephalopathy for 14 days which ranged from mild to moderate, sensitive to GI-side effects of lactulose or lactitol. This study was conducted in the United States of America, Poland, Hungary and the United Kingdom. The planned list of participants consisted of 112 subjects (56 in the group).

Definition of the main final criteria for evaluating effectiveness

An assessment was made of the mental state (Conn indicator) and neuromuscular function (degree of asterixis) in studies C, D and E, using the same criteria as described above for studies A and B.

Venous blood ammonia levels, NCT, and EEG results were ranked according to the increasing severity of the disease.

Study C: The primary outcome measure for evaluating efficacy for Study C was the PSE at the end of the study. The PSE index was a composite assessment, including assessments of mental state (Conn indicator), asterixis, levels of ammonia in venous blood, NCT and EEG.

Differences in the PSE index at the end of the study by treatment group using 600 mg, 1200 mg and 2400 mg of rifaximin daily were evaluated using analysis of covariates.

Study D: Four main outcome criteria for evaluating effectiveness were identified:

1. Improving the mental state (Conn indicator)

2. The PSE index.

3. Reduced levels of ammonia in venous blood

4. The decrease in the PSE index

Study E: The main final criterion for evaluating the effectiveness was the total effectiveness of the therapy, defined as the percentage of subjects showing an improvement in their mental state (Conn indicator) by at least 1 level (for example, the transition from a Conn indicator of 2 to a Conn indicator equal to 1 or 0) after completion of treatment compared to baseline.

Demographic and main characteristics

In study C, the average age was 55.2 years, 52.3 years, and 55.3 years in the groups using 600 mg, 1200 mg, and 2400 mg, respectively. In study D, the average age was 61.6 years and 62.9 years in the groups using rifaximin and lactitol, respectively. In Study E, the mean age was 53.6 years and 53.3 years in the groups using rifaximin and placebo, respectively.

Demographic characteristics were mostly similar in treatment groups in studies C, D, and E.

Table 8 summarizes the main characteristics for studies C, D, and E. Subjects in study D had more severe HE symptoms, as measured by mental status / Conn, degree of asterixis, and PSE index than subjects in study E. Also, the severity of the disease was more pronounced in D compared to C. For example, the proportion of subjects with indicators of mental status / Conn ≥2 before the study was 70% (rifaximin) and 60.3% (lactitol) in D, 14.6% (rifaximin) and 4 , 4% in E and 16.7%, 31.6% and 23.5% in the groups taking 600 mg, 1200 mg and 24 00 mg, in C. The time since diagnosis of HE disease (i.e., the duration of HE) was significantly longer in Study D than in Study E and Study C (see table 18).

Patient Distribution

During the 120-day safety update, 280 subjects were included in the study at 60 clinical trial centers. A total of 152 (54.3%) of these subjects moved out of the initial study (Study A), and 128 (45.7%) were new subjects. A total of 187 subjects (66.8%) were still continuing the study. Ninety-three subjects (33.2%) discontinued treatment earlier, and the main causes were death, liver transplant, subject request and adverse events.

Main characteristics

The main characteristics were mostly similar between the subjects in Study A and the subjects in Study B. Demographic characteristics are presented and the main characteristics are presented for new subjects using rifaximin in Study B.

Differences in the main characteristics between subjects of study A and study B were associated with differences in the criteria for inclusion in the study. Subjects had ≥1 confirmed episodes of HE within 12 months prior to screening for Study B compared with ≥2 episodes within 6 months prior to screening for Study A. According to these differences, when compared with Study A, subjects in Study B had more the long duration of ongoing confirmed remission of HE and a lower proportion of subjects with 2 or 3 confirmed episodes of HE before the study.

Subgroup analysis of time before a spontaneous, pronounced HE episode

Treatment with rifaximin reduced the risk of manifestation of spontaneous, pronounced episodes of HE for the totality of all the studied subgroups.

The risk ratio of the manifestation of spontaneous, pronounced HE in the rifaximin-treated group relative to the placebo-treated group (the main criterion for evaluating the effectiveness), 95% CIs and p values from the Cox proportional risk model are presented in FIG. 2. A risk ratio of less than 1 indicates that the result of treatment is in favor of rifaximin, and more than 1 is in favor of placebo.

The results of the time until the first spontaneous, pronounced HE episode for all Child-Pugh classifications before the start of the study are presented in Table 9. Elements of the overall Child-Pugh indicator, general indicators and classifications were obtained after the study. Treatment with rifaximin resulted in a significant reduction in the risk of a spontaneous, pronounced episode of HE when compared with placebo treatment for classes A, B or C Child-Pugh. A statistically significant effect of rifaximin treatment to reduce the risk of manifesting spontaneous, pronounced HE was found in the categories Child-Pugh A (5-6), B (7-9) and C (10-15).

Study A - Secondary Efficiency Tests

The rifaximin treatment resulted in a 50% reduction, when compared with placebo, of the risk of hospitalization due to HE (i.e., hospitalization directly attributable to HE or HE events occurring during hospitalization) during the 6-month treatment period (risk ratio = 0.500 95% CI: 0.287 to 0.873, p = 0.0129). Hospitalizations due to hepatic encephalopathy were reported for 19 of 140 subjects and 36 of 159 subjects in the groups receiving rifaximin and placebo, respectively. After normalizing the effects of the drug, the hospitalization rate due to HE was 51% lower (0.38 events / PEY, rifaximin compared to 0.78 events / PEY, placebo) in the rifaximin group.

Subjects in the rifaximin group experienced a 56% reduction in the risk of hospitalization due to HE (i.e., hospitalization directly attributable to HE alone) during the 6-month treatment period when compared with placebo (risk ratio = 0.438, 95% CI: 0.238 to 0.807, p = 0.0064). HE hospitalizations were reported for 15 of 140 subjects and 33 of 159 subjects in the rifaximin and placebo groups, respectively. The hospitalization rate attributable to HE was 0.30 occurrence / PEY in the rifaximin group compared with 0.72 occurrence / PEY in the placebo group.

CLDQ Fatigue Domain Indicators from Baseline at the End of Treatment in Study A

Evaluations of health-related quality of life were performed using an approved chronic liver disease questionnaire (CLDQ) for subjects with chronic liver disease.

Typically, CLDQ assays are performed by comparing changes from baseline to the last score in total and CLDQ domain scores between 2 treatment groups. However, using a simple change in baseline in this study, the analysis has the following limitations. Firstly, the questionnaire determines the status of the subject's quality of life for 2 weeks before filling out the questionnaire. By comparing the results of 2 weeks before the last assessment with the results of 2 weeks before the initial indicators (change from the initial analysis), changes throughout the course of the study are not recorded in the analysis. Secondly, most of the subjects in the study also had concomitant diseases associated with cirrhosis of the liver, which could potentially distort the results depending on the time of the complication, and if this happened during or shortly before the first or last assessment. Finally, subjects who showed a spontaneous episode of severe HE were excluded from the study according to the protocol and were given the latest CLDQ assessments during the final visit, which usually took place after resolving the HE event. Thus, for these subjects, CLDQ results could be similar to baseline. To account for these limitations, AUC analysis was performed using T _wa (AUC based on the exposure time in the study), since it allows the inclusion of CLDQ results over the full time period of the subject's participation in the study, in particular, before the spontaneous HE episode.

When the CLDQ results using T _wa were analyzed, the subjects in the rifaximin group had significantly less fatigue and a significantly better quality of life in general than the subjects in the placebo group. CLDQ results in favor of the rifaximin group were also demonstrated for the overall CLDQ domain score (p = 0.0093) and for each of the other constituent CLDQ domains, including abdominal symptoms (p = 0.0090), systemic symptoms (p = 0 , 0160), activity (p = 0.0022), emotional function (p = 0.0065), and anxiety (p = 0.0436).

It was shown that CLDQ results predict spontaneous pronounced episodes of HE, as determined by the main endpoint (Fig. 4). There were significant differences in the frequency distribution of T _wa (AUC, normalized by exposure time) for all CLDQ domains between subjects having spontaneous marked HE episodes and subjects not having spontaneous marked HE episodes. The average value of T _wa for each domain and the total indicator correlated with the presence or absence of a spontaneous pronounced HE episode.

Long-term efficacy (Study A and Study B)

Although study B was mainly designed to evaluate the long-term safety of 550 mg of rifaximin, additional evaluations of the effectiveness of Conn and the degree of asterixis were obtained at each visit and during a pronounced spontaneous episode of HE. Kaplan-Meyer analysis of the time to the first spontaneous pronounced episode of HE showed the constancy, duration, and reproducibility of the protective effect of rifaximin compared with placebo, as noted in Study A.

Time to spontaneous episode of HE in Study B - consistency with Study A

Kaplan-Meyer estimates of the time to the first spontaneous episode of HE expressed were similar between the group receiving rifaximin in Study A (PEY = 50 rifaximin) and the new subjects receiving rifaximin in Study B (PEY = 80 rifaximin) (p = 0,800 for differences in relative risks). Also, similar proportions of subjects had spontaneous pronounced episodes of HE in the rifaximin-treated group of Research A (22%, 31 of 140 [the rifaximin-treated group]) and in the new rifaximin-treated group of Research B (20.5%, 43 of 210). Given exposure, the proportion of spontaneous, expressed HE episodes was 0.62 events / PEY in the rifaximin-treated group from Study A when compared with 0.5 events / PEY for new rifaximin-treated subjects in Study B.

Time to spontaneous episode of HE in placebo-treated subjects in Study A who switched to therapeutic treatment with rifaximin in Study B

Subjects receiving from placebo A who went to study B were observed during the open study (n = 82). A comparison of Kaplan-Meyer estimates of the time to the first spontaneous pronounced HE episode between the placebo data obtained in Study A and the first 6 months of rifaximin treatment in Study B is shown in FIG. 5. The ratio of the number of cases of a spontaneous pronounced episode of HE during treatment with rifaximin relative to placebo treatment was 0.2112 (95% CI: from 0.1006 to 0.4432, p <0.0001 for intergroup differences in relative risks). These results mean a 79% reduction in the risk of manifesting a spontaneous marked HE episode during rifaximin treatment in Study B when compared to their previous placebo exposure in Study A. A spontaneous marked HE episode occurred in 14 of 82 cases over the course of 6 months of rifaximin treatment in Study B of compared with 39 of 82 cases during placebo treatment in Study A. The proportion of spontaneous episodes of HE was 1.5 events / PEY during placebo exposure in Study A and 0.4 events / PEY during rifaximin exposure in AND Investigation B.

Taken together, these results demonstrate that previously placebo-treated subjects enrolled in Study B experienced a similar protective effect against the occurrence of spontaneous HE episodes when compared with rifaximin-treated subjects in Study A and the rifaximin-treated group in Study B.

PSE index during short-term treatment

Improvements (i.e., a decrease) in the PSE index were observed in all treatment groups from the beginning to the end of the treatment in the optimal dose selection study, Study C. The average changes from the baseline in the PSE index at the end of treatment were -6.4%, -10 , 3% and -10.7% in the groups receiving a daily dose of rifaximin in the amount of 600 mg, 1200 mg and 2400 mg, respectively. In Study D, which compared a daily dose of 1200 mg of rifaximin with lactitol, a significant decrease in the PSE index was found in the rifaximin group when compared with the lactitol group (p = 0.0103). Also in Study D, the PSE efficacy index showed significant improvements in the rifaximin group compared with the lactitol group (p = 0.0083). PSE index changes were similar among rifaximin and placebo groups in Study E.

In FIG. Figure 6 shows the results of the PSE index at the beginning and end of studies C, D, and E.

Positive dynamics of Conn during short-term treatment

In study C (a study to determine the optimal dose), the results showed a statistical orientation showing a greater relative number of subjects with improved mental status (Conn indicator) in the 1200 mg group compared with the 600 mg group (p = 0.099 when using the model proportional odds). In addition, in the case of a daily dose of 2400 mg, a higher proportion of subjects showed an improvement in Conn compared with a daily dose of 600 mg (31.3% compared to 26.7% had Conn changes of -1 or -2).

Improvements in mental status (Conn score) did not differ significantly between the groups receiving rifaximin and lactitol in Study D; however, 3 of the main outcome indicators in Study D, a decrease in the PSE index, an improvement in the PSE efficiency index, and a decrease in venous blood ammonia levels showed significant, beneficial effects of rifaximin. The lack of a significant effect of rifaximin in improving the Conn score in Study D may be due to the short duration of therapeutic treatment with the investigational drug (10 days).

In study E, the absence of the effect of rifaximin in improving the Conn score may be due to the short duration of therapeutic treatment in this study (15 days) and mild HE symptoms at the start of the study. Subjects in Study E had mild HE symptoms, as measured by mental state / Conn, asterixis grade, and PSE, when compared to subjects in Study D or Study C.

Asterixis degree, NCT results, and overall response during short-term treatment

The percentage of subjects who had improved asterixis while on the drug increased with higher doses of rifaximin in Study C. In study D (rifaximin versus lactitol), the percentage of subjects with improved asterixis was similar among groups. In a rifaximin study versus a placebo Study E, more subjects had an improvement in the degree of asterixis in the rifaximin group compared with the lactitol group (39.1% versus 9.3%; p = 0.0097 for intergroup differences in benefit of rifaximin).

Changes in NCT scores were mostly similar across groups in each of the 3 studies.

The overall response to treatment was evaluated in Study D. The percentage of subjects considered cured (with normalized venous blood ammonia and mental Conn / 0) by the end of the study was higher in the rifaximin-treated group compared to the lactitol group (53.1% compared with 39.2%).

Conclusion of the results of short-term treatment in Studies C, D and E

In study C, a dose-dependent improvement trend in the PSE index (p = 0.056) and the mental state index / Conn was found, and the results of this study showed the effectiveness of a daily dose of rifaximin equal to 1200 mg (400 mg three times a day). These data, along with the results from published studies of rifaximin 1200 mg / day in the treatment of HE, suggest the feasibility of selecting a dose to consider study A and study B phase 3.

Study D revealed significant intergroup differences in changes in the PSE index and levels of ammonia in venous blood (both of which were the main endpoints) in favor of the rifaximin group compared with lactitol; and a higher proportion of rifaximin-treated subjects was considered cured by the end of treatment (with normal venous blood ammonia and mental status / Conn = 0).

In Study E, a significantly higher proportion of rifaximin-treated subjects had improvements in the degree of asterixis when compared with placebo-treated subjects; however, the results for the main final indicator, the proportion of subjects with improvements in the Conn indicator, did not significantly differ between the groups. Subjects in Study E had mild HE symptoms when compared with subjects in Study D.

Inclusion in a document by reference

The full contents of all references, patents pending patent applications and published patents cited in this application are expressly incorporated by reference.

Equivalents

Those skilled in the art will recognize or are able to detect, using standard experimental design, that numerous equivalents of the specific embodiments of the invention provided herein are described herein. Such equivalents are covered by the following claims.

Claims (6)

1. The use of rifaximin for the manufacture of a medicament for treating a subject suffering from, subject to, or in remission of hepatic encephalopathy (HE), comprising administering rifaximin for a period of about 24 weeks to 24 months at a dose of 550 mg twice daily. 2. The use of claim 1, wherein the subject is a person. 3. The use according to claim 1, where the clearance rate of rifaximin is reduced in a population of subjects with hepatic encephalopathy compared with a population of subjects without hepatic encephalopathy. 4. The use according to claim 1, where the rate of elimination of rifaximin is reduced in subjects with hepatic encephalopathy compared with subjects without hepatic encephalopathy. 5. The use according to claim 1, where the systemic effect of rifaximin is increased in a population of subjects with hepatic encephalopathy compared with a population of subjects without hepatic encephalopathy. 6. The use of claim 1, wherein the level of rifaximin serum is increased in a population of subjects with hepatic encephalopathy compared with a population of subjects without hepatic encephalopathy.

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