RU2781242C2 - Methods for treatment of gaucher disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: methods for the treatment of Gaucher disease in a patient, which is a fast CYP2D6 metabolizer with light hepatic insufficiency or with moderate or severe renal insufficiency, are proposed. The use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt per the main form is proposed for administration once a day for the treatment of Gaucher disease in a patient who needs it, in a combination with a weak CYP2D6 inhibitor or with a strong, moderate, or weak CYP3A inhibitor. The use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt per the main form is proposed for administration twice a day for the treatment of Gaucher disease in a patient, where the patient is a fast CYP2D6 metabolizer with light hepatic insufficiency or with moderate or severe renal insufficiency.

EFFECT: proposed group of inventions provides safe use of eliglustat for the treatment of Gaucher disease in patients with hepatic or renal insufficiency.

9 cl, 6 dwg, 4 tbl, 3 ex

Description

The field of technology to which the invention belongs

This document provides methods for the treatment of Gaucher's disease in patients with renal or hepatic insufficiency.

Background of the invention

Glycosphingolipids (GSLs) are a class of naturally occurring compounds that have a variety of biological functions, including the ability to stimulate cell growth, cell differentiation, adhesion between cells or between cells and matrix proteins, binding of microorganisms and viruses to cells, and metastasis of tumor cells. GSLs are formed from glucosylceramide (GlcCer), which is synthesized from ceramide and UDP-glucose by the enzyme UDP-glucose: N -acylsphingosine glucosyltransferase (GlcCer-synthase). The structure of ceramide is shown below:

The accumulation of GSL is associated with a number of diseases, including diseases of Tay-Sachs, Gaucher and Fabry (see, for example, US patent No. 6051598). Compounds that inhibit glucosylceramide (GlcCer) synthase can decrease GSL concentrations and have been reported to be useful in treating a patient with one of the aforementioned diseases.

Eliglustat is a glucosylceramide synthase inhibitor currently approved in the United States as an oral first-line treatment for adults with Gaucher disease type 1 (GD1) who are rapid metabolizers (EM), intermediate metabolizers (IM), or slow metabolizers (PM). ) by CYP2D6.

Eliglustat (chemical name: N-((1 R ,2 R )-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)octanamide) has the structural formula (I):

(I).

(I).

For example, US Pat. No. 7,196,205 describes the preparation and physical and biological properties of a compound having formula (I).

Eliglustat is marketed in the United States under the brand name Cerdelga® as a hemitartrate salt having the following formula (Ia):

(Ia),

(Ia)

which is also referred to herein as eliglustat tartrate.

The preparation of eliglustat tartrate is described, for example, in WO2011/066352.

The use of eliglustat or a pharmaceutically acceptable salt thereof for the treatment of patients who are rapid metabolizers (EM), intermediate metabolizers (IM) or slow metabolizers (PM) of CYP2D6 is described in WO 2011/066352.

Eliglustat has not previously been recommended by the FDA and EMA in GD1 patients with moderate to severe hepatic impairment or renal impairment due to lack of data for dosage recommendations. It has recently been surprisingly found that eliglustat can be safely used to treat GD1 in some patients with hepatic or renal insufficiency.

Brief description of the invention

Accordingly, this document provides a method of treating Gaucher disease comprising administering to a patient in need thereof an effective amount of eliglustat or a pharmaceutically acceptable salt thereof, wherein said patient is a rapid CYP2D6 metabolizer with mild hepatic impairment (Child-Pugh class A cirrhosis). In one aspect, the effective amount is a twice daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, based on the base form. In one aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is a method of treating Gaucher disease comprising administering to a patient in need thereof an adjusted effective amount of eliglustat or a pharmaceutically acceptable salt thereof, wherein said patient is a rapid CYP2D6 metabolizer with mild hepatic impairment, and wherein said patient is concomitantly taking a drug. a drug that is a weak inhibitor of CYP2D6. In one aspect of this embodiment, the adjusted effective amount is a once-daily administration dose of 84 mg of eliglustat, or a pharmaceutically acceptable salt thereof, based on the base form. In one aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is a method of treating Gaucher disease comprising administering to a patient in need thereof an adjusted effective amount of eliglustat or a pharmaceutically acceptable salt thereof, wherein said patient is a rapid CYP2D6 metabolizer with mild hepatic impairment, and wherein said patient is concomitantly taking a drug. an agent that is a strong, moderate or weak inhibitor of CYP3A. In one aspect of this embodiment, the adjusted effective amount is a once-daily administration dose of 84 mg of eliglustat, or a pharmaceutically acceptable salt thereof, based on the base form. In one aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is a method of treating Gaucher disease comprising administering to a patient in need thereof an effective amount of eliglustat or a pharmaceutically acceptable salt thereof, wherein said patient is a rapid CYP2D6 metabolizer with mild, moderate or severe renal impairment. In one aspect of this embodiment, the effective amount is a twice daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, based on the base form. In one aspect, Gaucher's disease is type 1 Gaucher's disease.

BRIEF DESCRIPTION OF GRAPHICS

Figure 1 shows the individual values of C _max after taking a single dose of 84 mg of eliglustat in accordance with the study shown in example 1.

Figure 2 shows the individual AUC values after taking a single dose of 84 mg of eliglustat in accordance with the study shown in example 1.

Figure 3 shows the concentration-time profiles of eliglustat (mean±SD) in the deficient group following a single dose of 84 mg eliglustat in accordance with the study conducted in Example 1 (linear-linear scale).

Figure 4 shows the concentration-time profiles of eliglustat (mean±SD) in the deficient group following a single dose of 84 mg eliglustat in accordance with the study conducted in Example 1 (linear logarithmic scale).

Figure 5 shows the individual values of C _max after taking a single dose of 84 mg of eliglustat in accordance with the study conducted in example 3.

Figure 6 shows individual AUC values after taking a single dose of 84 mg of eliglustat in accordance with the study shown in example 3.

Detailed description of the invention

Used above and throughout the description of the present invention, the following expressions, unless otherwise indicated, should be understood as having the following meanings:

in the context of this document, “co-administered”, “co-administration”, “in combination” and “simultaneous administration” means administered or administered at the same time, on the same day or within 24 hours, in particular within 12 hours.

In the context of this document, "effective amount" means the amount of eliglustat that will be recommended to the patient to take, or the doctor will prescribe for taking to the patient if the patient does not have liver or kidney failure. In one aspect, the effective amount of eliglustat is the US Food and Drug Administration approved amount of 84 mg twice daily for patients who are CYP2D6 EM or IM and administered once daily dose of 84 mg for patients who are PM. The dose of eliglustat is calculated in terms of the main form. It should be understood that eliglustat can be administered in the form of a pharmaceutically acceptable salt, in particular in the form of hemitartrate, while the amount of salt administered must be adjusted accordingly.

In the context of this document, "patient" means a person.

"Pharmaceutical salt" in the context of this document means that the salts of the compounds of the present invention can be used in drugs.

In the context of this document, the wording "compound for use...", for example, should be understood as equivalent to the wording "use of the compound for..." or "use of the compound for the preparation of a medicinal product intended for use in...".

In certain embodiments, the patient's liver function is assessed according to the Child-Pugh classification, which defines three classes of liver cirrhosis. According to this classification system, scores are assigned to indicators for each of five categories: total bilirubin level, serum albumin level, prothrombin time, ascites and hepatic encephalopathy. Each indicator is assigned a score of 1, 2, or 3, and the sum of the five scores equals the Child-Pugh score. The Child-Pugh score is used to classify liver failure by assigning patients a Child-Pugh score of Child-Pugh A (mild liver failure), Child-Pugh B (moderate liver failure), and Child-Pugh C - I drink (severe liver failure).

In certain embodiments, the patient's renal function is determined by creatinine clearance calculated according to the Cockcroft-Gault formula, where the subject or patient with creatinine clearance > 80 ml/min has normal renal function, the subject or patient with creatinine clearance 50-80 ml/min has mild renal impairment, a subject or patient with a creatinine clearance of 30-50 ml/min has moderate renal impairment, a subject or patient with a creatinine clearance <30 ml/min has severe renal impairment.

Eliglustat is metabolized in the liver, mainly by enzymes of the cytochrome P450 system. Cytochrome P450-dependent enzymes ("CYP") are the main hepatic enzymes of xenobiotic metabolism. There are eleven cytochromes P450 of xenobiotic metabolism expressed in the human liver (i.e. CYP1A2, CYP2A6, CYP2B6, CYP2C8/9/18/19, CYP2D6, CYP2E1 and CYP3A4/5). Primarily CYP2D6 and to a lesser extent CYP3A4 are the primary cytochrome P450 isoforms that are responsible for the metabolism of eliglustat and its pharmaceutically active salts such as eliglustat tartrate. The level of activity of some P450 enzymes, such as CYP2D6, differs depending on the individual CYP2D6 phenotype. For example, individuals can be classified as slow, intermediate, fast, and ultrafast metabolizers for CYP2D6.

The patient is usually identified as a slow, intermediate, fast, or ultrarapid CYP2D6 metabolizer by genotyping, although in rare cases the genotype cannot be determined (indeterminate metabolizer).

For example, the patient may be a slow P450 metabolizer due to low expression of the P450 enzyme. In such cases, low expression can be assessed by determining the expression of the P450 enzyme in the patient, ie, genotyping the patient for the P450 enzyme. For example, CYP2D6 expression is usually measured using PCR (McElroy et.al. "CYP2D6 Genotyping as an Alternative to Phenotyping for Determination of Metabolic Status in a Clinical Trial Setting", AAPS Pharmsi (2000) 2(4) article 33) or microarray-based pharmacogenomic testing. Therefore, the patient can be genotyped for P450 expression (eg, CYP2D6) prior to treatment, which is convenient, and an adjusted effective amount of the drug administered if necessary.

There are four predicted phenotypes for the CYP2D6 gene:

in the context of this document, a "CYP2D6 slow metabolizer" carries two mutant alleles, resulting in a complete loss of enzyme activity.

In the context of this document, a "CYP2D6 intermediate metabolizer" has one down-regulated allele and one null allele.

As used herein, a "rapid CYP2D6 metabolizer" has at least one and no more than two functionally active alleles.

In the context of this document, "ultra-rapid CYP2D6 metabolizer" carries multiple copies (3-13) of functionally active alleles and results in excess enzymatic activity.

Because eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A, eliglustat concentrations may be increased in patients co-administered with certain medicinal products that are inhibitors of the CYP2D6 enzyme. Examples of weak inhibitors of CYP2D6 include, but are not limited to: escitalopram, abiraterone, diphenhydramine, amiodarone, deramciclane, desvenlafaxine, fosdevirin, daclatasvir/asunaprevir/beclabuvir, oral contraceptives, osilodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, flulodoxib, celecoxib , gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, escitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir/ritonavir, sarpogrelat, artesunate/pyronaridin, imatinib, and febuxostat. Examples of mild inhibitors of CYP2D6 include, without limitation: duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone, rolapitant, cimetidine, and tipranavir/ritonavir. Examples of strong inhibitors of CYP2D6 include, without limitation: paroxetine, fluoxetine, quinidine, bupropion, and dacomitinib.

Patients who are slow metabolizers of CYP2D6 have little or no CYP2D6 function, so in these patients, eliglustat metabolism occurs primarily via the CYP3A pathway. The metabolism of eliglustat in these patients may be further reduced by treatment with certain drugs that are inhibitors of the CYP3A enzyme. For example, examples of weak inhibitors of CYP3A include, without limitation: amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and ranolazine. Examples of mild CYP3A inhibitors include, without limitation: erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine, amprenavir, casopitant, crizotinib, faldaprevir, ledipasvir, netupitant, nilotinib, tofisopam, cimethidinone, and cyclosporine. Examples of strong CYP3A inhibitors include, without limitation: ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir, idelalisib, mibefradil, nefazodone, nelfinavir, elvitegravir/ritonavir, danopravir/ritonavir and troleandomycin.

Another embodiment provided herein is a method of providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof is provided along with information indicating that they are useful in the treatment of patients with Gaucher disease, in particular adult patients. with Gaucher disease type 1, and where dose adjustment is not required in cases where the indicated patient is a rapid CYP2D6 metabolizer with mild hepatic insufficiency. In one aspect of this embodiment, the recommended or effective amount is 84 mg of eliglustat, based on base, administered twice daily.

Another embodiment provided herein is a method of providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof is provided along with information indicating that they are useful in the treatment of patients with Gaucher disease, in particular adult patients. with type 1 Gaucher disease, and where the effective amount should be reduced to a adjusted effective amount in cases where the specified patient is a rapid CYP2D6 metabolizer with mild hepatic insufficiency and while administering a weak inhibitor of CYP2D6 or a strong, moderate or weak inhibitor of CYP3A. In one aspect of this embodiment, the adjusted effective amount is a single daily dose of 84 mg of eliglustat on a base basis.

Another embodiment provided herein is a method of providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof is provided along with information indicating that eliglustat or a pharmaceutically acceptable salt thereof is contraindicated IM or PM on CYP2D6 with any degree of hepatic impairment and CYP2D6 EM with moderate or severe hepatic impairment.

Another embodiment provided herein is a method of providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof is provided along with information indicating that they are useful in the treatment of patients with Gaucher disease, in particular adult patients. with type 1 Gaucher disease, and where dose adjustment is not required in cases where the specified patient is a rapid CYP2D6 metabolizer with mild, moderate or severe renal insufficiency. In one aspect of this embodiment, the recommended or effective amount is 84 mg of eliglustat, based on base, administered twice daily.

Another embodiment provided herein is a method of providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof is provided along with information indicating that eliglustat or a pharmaceutically acceptable salt thereof is not recommended or should be avoided. CYP2D6 EM with end-stage renal disease and CYP2D6 IM or PM with mild, moderate, or severe renal impairment or end-stage renal disease.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package leaflet contained in the packaging material stating that eliglustat or its pharmaceutically acceptable salt is contraindicated for CYP2D6 intermediate metabolizers (IM) or slow metabolizers (PM) with any degree of hepatic insufficiency and rapid metabolizers (EM) for CYP2D6 with moderate or severe hepatic impairment.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package insert contained in the packaging material stating that no dose adjustment of eliglustat or its pharmaceutically acceptable salt is required for CYP2D6 rapid metabolizers (EM) with mild hepatic impairment.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package leaflet contained in the packaging stating that eliglustat or its pharmaceutically acceptable salt is contraindicated in rapid metabolizers (EM) with mild hepatic impairment taking a strong or moderate inhibitor of CYP2D6; and for CYP2D6 rapid metabolizers (EM) with mild hepatic impairment taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor, a dose of 84 mg eliglustat administered once daily should be considered.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package insert contained in the packaging material stating that no dose adjustment of eliglustat or its pharmaceutically acceptable salt is required for CYP2D6 rapid metabolizers with mild, moderate or severe renal insufficiency.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package insert contained in the packaging stating that eliglustat or its pharmaceutically acceptable salt is not recommended or should be avoided by CYP2D6 rapid metabolizers (EM) with end-stage renal disease.

Another embodiment presented herein is an article comprising:

a) packaging material;

b) eliglustat or a pharmaceutically acceptable salt thereof, and

c) the label or package leaflet contained in the packaging stating that eliglustat or its pharmaceutically acceptable salt should be avoided by intermediate metabolizers (IM) or slow metabolizers (PM) with mild, moderate or severe renal impairment or end stage kidney failure.

Another embodiment presented herein is a package containing eliglustat or a pharmaceutically acceptable salt thereof and a label, said label containing a printed statement informing the potential consumer that eliglustat or its pharmaceutically acceptable salt i) is indicated for the treatment of a disease Gaucher type 1 and ii) are contraindicated in CYP2D6 intermediate (IM) or slow metabolizer (PM) metabolizers with any degree of hepatic impairment and CYP2D6 rapid metabolizers (EM) with moderate or severe hepatic impairment.

Another embodiment presented herein is a package containing eliglustat or a pharmaceutically acceptable salt thereof and a label, said label containing a printed statement informing the potential consumer that eliglustat or its pharmaceutically acceptable salt i) is indicated for the treatment of a disease Gaucher type 1 and ii) are contraindicated in rapid metabolizers (EM) with mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor. For CYP2D6 rapid metabolizers (EM) with moderate hepatic impairment taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor, a dose of 84 mg eliglustat administered once daily should be considered.

Another embodiment presented herein is a package containing eliglustat or a pharmaceutically acceptable salt thereof and a label, said label containing a printed statement informing the potential consumer that eliglustat or its pharmaceutically acceptable salt i) is indicated for the treatment of a disease Gaucher type 1 and ii) are not recommended or should be avoided by CYP2D6 rapid metabolizers (EM) with end stage renal disease (ESRD).

Another embodiment presented herein is a package containing eliglustat or a pharmaceutically acceptable salt thereof and a label, said label containing a printed statement informing the potential consumer that eliglustat or its pharmaceutically acceptable salt i) is indicated for the treatment of a disease Type 1 Gaucher and ii) are not recommended for intermediate metabolizers (IM) or slow metabolizers (PM) with mild, moderate or severe renal impairment or end-stage renal disease, and eliglustat is not recommended or should be avoided by rapid metabolizers (EM) by CYP2D6 with end-stage renal disease.

Another embodiment provided herein is a method of treating Gaucher's disease comprising administering an adjusted effective amount of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof, in combination with a weak CYP2D6 inhibitor, wherein said patient is a rapid CYP2D6 metabolizer and wherein: This patient has a mild degree of hepatic insufficiency. In one aspect of this embodiment, the adjusted effective amount of eliglustat, or a pharmaceutically acceptable salt thereof, is a dose of 84 mg of eliglustat, based on the base form, administered once daily. In another aspect, the weak inhibitor of CYP2D6 is escitalopram, abiraterone, diphenhydramine, amiodarone, deramciclane, desvenlafaxine, fosdevirin, daclatasvir/asunaprevir/beclabuvir, oral contraceptives, osilodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, flulodamine, celecoxib, celecoxib , gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, escitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir/ritonavir, sarpogrelat, artesunate/pyronaridin, imatinib, or febuxostat. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

Another embodiment provided herein is a method of treating Gaucher disease comprising administering an adjusted effective dose of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof in combination with a strong, moderate, or weak CYP3A inhibitor, wherein said patient is a rapid CYP2D6 metabolizer. , and where the specified patient has a mild degree of liver failure. In one aspect of this embodiment, the adjusted effective amount of eliglustat, or a pharmaceutically acceptable salt thereof, is a dose of 84 mg of eliglustat, based on the base form, administered once daily. Examples of weak CYP3A inhibitors include amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and ranolazine. In one aspect, the mild CYP3A inhibitor is selected from the group consisting of erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine, amprenavir, casopitant, crizotinib, faldaprevir, ledipasvir, ledipasvir, dronedarone, cimetidine and cyclosporine. In one aspect, a strong CYP3A inhibitor is selected from the group consisting of ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir, idealalisib, mibefradil, nefazodone, elvitegravir/ritonavir, danopravir/ritonavir and troleandomycin. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is eliglustat, or a pharmaceutically acceptable salt thereof, for use in the treatment of Gaucher disease in a patient where the patient is a rapid CYP2D6 metabolizer with mild hepatic impairment. In one aspect, eliglustat, or a pharmaceutically acceptable salt thereof, is administered in an effective amount, wherein the effective amount is a twice daily dose of 84 mg based on the base substance. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is eliglustat, or a pharmaceutically acceptable salt thereof, for use in the treatment of Gaucher disease in a patient, where the patient is a rapid CYP2D6 metabolizer with mild hepatic insufficiency, and where said patient is concomitantly taking a drug that is a weak inhibitor of CYP2D6 . In one aspect, eliglustat or a pharmaceutically acceptable salt thereof is administered in an adjusted effective amount, wherein the adjusted effective amount is a once daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, based on the base form. In another aspect, the weak inhibitor of CYP2D6 is selected from escitalopram, abiraterone, diphenhydramine, amiodarone, deramcilan, desvenlafaxine, fosdevirin, daclatasvir/asunaprevir/beclabuvir, oral contraceptives, osilodrostate, propafenone, ritonavir, cimetidine, clobazam, cobicistat, ritonavir, cimetidine, clobazam, cobicistat, ritonavir, celorekvokserin , gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, escitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir/ritonavir, sarpogrelat, artesunate/pyronaridine, imatinib or febuxostat. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is eliglustat, or a pharmaceutically acceptable salt thereof, for use in the treatment of Gaucher disease in a patient, where the patient is a rapid CYP2D6 metabolizer with mild hepatic impairment, and where said patient is concomitantly taking a drug that is strong, moderate or a weak inhibitor of CYP3A. In one aspect of this embodiment, eliglustat or a pharmaceutically acceptable salt thereof is administered in an adjusted effective amount, wherein the adjusted effective amount is a once daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, based on the base form. In one aspect, the weak CYP3A inhibitor is selected from, for example, amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and ranolazine. In one aspect, the mild CYP3A inhibitor is selected, for example, from the group consisting of erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, and cimetidine. In one aspect, a strong CYP3A inhibitor is selected, for example, from the group consisting of ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazivin, telithromycin, conivaptan, and boceprevir. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

In another embodiment, provided herein is eliglustat, or a pharmaceutically acceptable salt thereof, for use in the treatment of Gaucher disease in a patient, where the patient is a rapid CYP2D6 metabolizer with mild, moderate, or severe renal impairment. In one aspect of this embodiment, eliglustat or a pharmaceutically acceptable salt thereof is administered in an effective amount, wherein the effective amount is a twice daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, based on the base form. In another aspect, Gaucher's disease is type 1 Gaucher's disease.

For their therapeutic use, eliglustat and its pharmaceutically acceptable salts are typically formulated into pharmaceutical compositions.

These pharmaceutical compositions contain eliglustat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

These excipients are selected according to the pharmaceutical form and the desired route of administration from the usual excipients known to those skilled in the art.

As an example, the dosage of eliglustat or its pharmaceutically acceptable salt in capsule form may be as follows: an oral capsule containing 84 mg of eliglustat (equivalent to 100 mg of the hemitartrate salt), microcrystalline cellulose, lactose monohydrate, hypromellose, and glyceryl behenate.

The present invention can be better understood by reference to the following non-limiting examples, which are illustrative of the present invention. However, this should in no way be construed as limiting the scope of the present invention.

Example 1

A multicentre, open-label, single oral dose study of eliglustat tartrate was conducted in appropriate (by body weight and cytochrome P450 [CYP] 2D6 phenotype) subjects with mild to moderate HI and normal liver function (healthy subjects) to investigate the effect of mild to moderate hepatic impairment. (HI) on the pharmacokinetics (PK) of eliglustat.

Approximately 8 subjects were planned to be recruited into each group with HI (mild or moderate HI) and 8 subjects with normal liver function corresponding to subjects with deficiency in weight and CYP2D6 phenotype. At least 6 CYP2D6 rapid metabolizers (EMs) were recruited into each deficiency group, and the remaining 2 subjects were recruited according to the following preference: at least 20 subjects were to be screened for each deficiency group and no more than 2 were recruited if identified. slow metabolizers (PM) CYP2D6. If less than 2 PM was identified, then no more than 2 CYP2D6 intermediate metabolizers (IMs) had to be recruited from a total of 8 subjects per group. If less than 2 PM or IM were identified, then no more than 2 additional EMs were recruited out of a total of 8 subjects per group. If 2 PM was detected before screening 20 subjects, then screening could be stopped. If an eligible subject with PM was identified after fulfilling the above requirements and recruiting 8 subjects into a deficient group, that subject could still be included in that deficient group.

CYP2D6 EMs and IMs were to receive a single dose of 100 mg eliglustat tartrate, while CYP2D6 PMs were to receive a single dose of 50 mg eliglustat tartrate.

Diagnosis and inclusion criteria:

Subjects with HI: male subjects (body weight 50.0 to 125.0 kg inclusive) or female subjects (body weight 40.0 to 110.0 kg inclusive) aged 18 to 79 years inclusive, with index body weight from 18.0 to 37 kg/m ² inclusive; who have stable chronic liver failure, which was assessed by history, physical examination and laboratory parameters; with moderate HI (defined on the Child-Pugh scale with a score of 7 to 9 points inclusive) or with a mild degree of HI (defined on the Child-Pugh scale with a score of 5 to 6 inclusive).

Healthy subjects: male subjects or female subjects aged 18 to 79 inclusive; body weight within 15% of the body weight of eligible subjects with HI and body mass index between 18.0 and 37 kg/m², inclusive; healthy subjects also matched the HI groups for the CYP2D6 phenotype predicted by the genotype.

Dosing schedule:

CYP2D6 EM or IM subjects with mild to moderate HI and eligible healthy subjects were administered a single dose of 100 mg eliglustat tartrate capsule (equivalent to 84 mg eliglustat).

CYP2D6 PM subjects with mild to moderate HI and eligible healthy subjects were administered a single dose of 50 mg eliglustat tartrate per capsule (equivalent to 42 mg eliglustat).

Criteria for evaluation:

Pharmacokinetics: The following PK parameters were calculated for plasma concentrations of eliglustat using non-compartmental methods: maximum observed plasma concentration (C _max ), area under the plasma concentration-time curve calculated using the trapezoidal method from time zero to time corresponding to the last measured concentration t _last (AUC _last ), time to reach C _max (t _max ), area under the plasma concentration-time curve extrapolated to infinity (AUC), terminal half-life associated with end-stage slope λz (t _1/2z ), the time corresponding to the last concentration exceeding the limit of quantitation (t _last ), the apparent total plasma clearance of the drug (CL/F) and the apparent volume of distribution during the final (λz) phase (Vz/ F).

Sampling times for pharmacokinetic studies and bioanalytical methods:

blood samples were taken to assess plasma concentrations of eliglustat at the following time points: before taking the drug and after 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours after taking the drug.

Plasma concentrations of eliglustat were determined using a validated liquid chromatography technique with tandem mass spectrometry with a lower limit of quantitation of 0.2 ng/mL.

Statistical methods:

Pharmacokinetics:

Eliglustat PK parameters were summarized using descriptive statistics for each cohort and for each CYP2D6 phenotype. For log-transformed C _max , AUC _last , AUC, t _1/2z , CL/F, and Vz/F, the effect of liver failure on eliglustat PK parameters after single dose eliglustat tartrate was analyzed using a linear fixed effects model for EM subjects by CYP2D6. For each parameter, an interval estimate and a 90% confidence interval (CI) of the geometric mean for each sample were determined, as well as for the ratio of geometric means for each group with liver failure versus normal control group.

Safety:

The safety assessment was based on a review of individual values (clinically significant abnormalities) and descriptive statistics (spreadsheets). All safety analyzes were performed using a safety sample and were based on treatment phase data (defined as the time from study drug administration [IMP] up to and including the Day 3 visit). Potentially clinically significant abnormalities (PCSA) of laboratory data, vital signs, and ECG data were analyzed using the May 24, 2014 version of the PCSA list. Electrocardiogram parameters were obtained by automatic 12-lead ECG readings and analyzed as initial parameter values and changes from baseline. Baseline data and changes from baseline in vital signs were summarized using descriptive statistics by sample group and time point. All individual data on biochemistry, hematology and qualitative urine tests were recorded in writing.

Adverse events were coded according to the Medical Regulatory Dictionary (MedDRA v.19.1) and classified into predefined standard categories according to chronological criteria:

• pre-treatment adverse events (AE), defined as AEs that occur, progress (as judged by the investigator), or become severe in the pre-treatment phase (defined as the time interval between signing the informed consent and taking the IMP [excluding taking] );

• AE arising during treatment (TEAE), defined as AE that occurred, progressed or became severe during the treatment phase;

• Post-treatment AE, defined as AE that occurred, progressed, or became severe in the post-treatment phase (defined as the time after the Day 3 visit to completion of EOS).

All AEs reported in the study were recorded in writing and ranked by subject, date and time of occurrence.

The number and percentage of subjects with TEAE were recorded by sample group, primary system organ class (SOC), preferred term (PT), and AE diagnosis.

Sample characteristics:

Eight subjects were recruited into each group. Seven CYP2D6 EMs and 1 CYP2D6 IM were recruited into the moderately deficient group and into the corresponding healthy group, and 6 CYP2D6 EMs and 2 CYP2D6 IMs were recruited into the mildly deficient group.

Results of a pharmacokinetic study:

mean ± SD (geometric mean) [CV%] of eliglustat PK parameters in EM subjects on CYP2D6 after a single dose of 100 mg eliglustat tartrate

Eliglustat in plasma EM subjects by CYP2D6 Subjects IM by CYP2D6 Parameter Healthy Subjects Mild HI Moderate HI Healthy Subjects Mild HI Moderate HI N 7 6 7 one 2 one _Cmax 10.4 ± 7.40 22.4 ± 30.2 39.5 ± 43.4 75.9 35.9 35.6 (ng/ml) (8.81) [70.9] (10.7) [135.1] (24.8) [110.0] (26.7, 45.1) t _max ^a 2.50 1.75 4.00 2.50 2.00 1.52 (h) (1.00-3.00) (1.00-6.00) (1.00-6.00) (2.00, 2.00) AUC _last 63.9 ± 47.1 166 ± 285 536 ± 642 568 334 197 (ng⋅h/mL) (54.7) [73.7] (64.3) [171.3] (293) [119.6] (187, 481) AUC 69.0 ± 49.1 172 ± 293 575 ± 696 578 346 208 (ng⋅h/mL) (59.5) [71.2] (68.5) [170.5] (307) [121.0] (190, 501) t _1/2z 7.08 ± 0.881 7.25 ± 1.46 10.5±2.25 8.48 9.34 5.87 (h) (7.03) [12.5] (7.13) [20.1] (10.3) [21.4] (8.27, 10.4) CL/F 1570 ± 628 1980±1440 416 ± 295 146 306 406 (l/h) (1420) [40,1] (1230) [72.8] (275) [70.9] (168, 444) Vz/F 16030 ± 6020 20000±15600 5840 ± 4130 1790 3910 3430 (l) (14400) [37.5] (12700) [78.2] (4090) [70.7] (2520, 5300) t _last ^a 24.00 30.00 48.00 48.00 48.00 24.00 (h) (24.00-24.05) (24.00-48.00) (36.00-48.00) (48.00, 48.00) a Median value (Min - Max)
b Average value (Min, Max) for N=2 Point estimates of geometric mean ratio with 90% CI in EM subjects by CYP2D6

Compared with healthy CYP2D6 EM subjects, the mean _Cmax and AUC for eliglustat were slightly higher in CYP2D6 EMs with mild HI (1.22- and 1.15-fold, respectively) and markedly higher in subjects with moderate HI (in 2.81 and 5.16 times, respectively) after a single dose of 100 mg eliglustat tartrate. Mean t _1/2z values were similar in moderate HI subjects and healthy subjects, but were more increased in moderate HI subjects (10.5 hours versus 7.08 hours).

Security results:

a total of 6 mild TEAEs were observed in 5 subjects. The investigator considered that four TEAEs in 3 subjects were associated with study drug: dysgeusia in 2 moderate HI subjects and nausea and headache in 1 healthy subject. There were no reports of serious adverse events, while there were no cases of death or other significant AE. No treatment-induced PCSA was found to be clinically significant in terms of laboratory or vital signs and ECG.

Example 2

A physiologically based pharmacokinetic (PBPK) model, developed using the results of preclinical and clinical studies of eliglustat, was verified using experimental data from single doses in both healthy and patients with hepatic insufficiency from the study described in example 1. This PBPK model was used to predict the effects of eliglustat after repeated doses of eliglustat in CYP2D6 EM subjects with mild to moderate HI, as well as healthy CYP2D6 EM subjects (without HI) for comparison. PK simulation of eliglustat was performed in 10 virtual trials in 10 subjects/category after repeated 84 mg twice daily (BID) or once daily (QD) oral dose of eliglustat alone for 8 days, with simulation results presented in Table one.

Table 1. Simulated mean (range of 10 means of 10 trials) at steady state exposure after oral eliglustat in EM by CYP2D6 (healthy subjects, mild HI and moderate HI)

EM by CYP2D6 84 mg BID ^a 84 mg ^QDa _Cmax AUC _0-tau Ratio ^b (HI/healthy subjects) _Cmax AUC _0-tau (ng/ml) (ng.h/ml) _Cmax AUC _0-tau (ng/ml) (ng.h/ml) Healthy Subjects 27 199 -- -- 17.9 146 (17.0, 37.2) (114, 291) (12.7, 22.2) (94.5, 203) Mild HI 64.2 568 2.38 2.85 32.9 351 (39.1, 97.0) (322, 893) (22.2, 49.5) (215, 606) Moderate HI 173 1760 6.41 8.86 83.5 1270 (127, 235) (1270, 2470) (59.2, 115) (852, 1890) AUC0-tau = area under the plasma concentration-time curve from time zero to the end of the dosing interval of 12 hours for BID and 24 hours for QD (AUC0-tau represents AUC0-12 for BID and AUC0-24 for QD mode); BID=twice a day; Cmax=maximum observed plasma concentration; EM=rapid metabolizer; QD = once a day; HI=liver failure.
a: values are given for 3 significant results.
b: ratio of average exposure values.

To ensure that eliglustat exposure remains within the range of eliglustat exposure that has been demonstrated to be safe and effective in clinical studies, the effects of 84 mg QD eliglustat when co-administered with CYP2D6 inhibitors or CYP3A inhibitors were evaluated using PBMK modeling on subjects EM on CYP2D6 with mild HI. Various options for co-administration of 84 mg QD eliglustat with CYP2D6 inhibitors or CYP3A inhibitors were modeled using the "Simcyp" built-in inhibitor model with minor modifications if necessary. Paroxetine, terbinafine, and ritonavir were used as strong, moderate, and weak CYP2D6 inhibitors, respectively, while ketoconazole, fluconazole, and fluvoxamine were used as strong, moderate, and weak CYP3A inhibitors, respectively. PK modeling of eliglustat was performed with 10 virtual trials in 10 CYP2D6 EM subjects with mild HI after repeated administration of 84 mg QD eliglustat alone for 8 days (day 1 to day 8) and co-administered with CYP2D6 or CYP3A inhibitors for an additional 7 or 10 days (day 9 - day 15 or day 9 - day 18). PBPK model predicted mean eliglustat exposures (mean range for 10 virtual trials) in CYP2D6 EMs with mild HI when eliglustat was co-administered with CYP2D6 or CYP3A inhibitors are presented in Table 2. Simulated exposures in healthy EMs were also included for comparison. and EM with moderate HI after eliglustat 84 mg twice daily alone.

Table 2 Simulated mean (range of 10 means from 10 trials) at steady state exposure in CYP2D6 EMs (healthy and mild HI) after oral eliglustat with and without CYP2D6 or CYP3A inhibitors

Eliglustat Sample Type of CYP inhibitor CYP inhibitor (dose) Eliglustat +
CYP inhibitor C _max ^{a AUC} _0-tau (ng/ml) (ng⋅h/mL) 84 mg BID Healthy Subjects Missing -- 27 199 (17.0, 37.2) (114, 291) 84 mg BID Mild HI Missing -- 64.2 568 (39.1, 97.0) (322, 893) 84 mg QD Mild HI Strong inhibitor of CYP2D6 Paroxetine 155 2630 (30 mg QD) (119, 192) (1840, 3450) 84 mg QD Mild HI Strong inhibitor of CYP3A Ketoconazole 71.7 1060 (400 mg QD) (32.8, 138) (377, 2380) 84 mg QD Mild HI Moderate inhibitor of CYP2D6 Terbinafine 96.9 1350 (250 mg QD) (82.1, 110) (1080, 1580) 84 mg QD Mild HI Moderate inhibitor of CYP3A Fluconazole 53.5 700 (loading dose 400 mg + 200 mg QD) (31.6, 83.7) (342, 1240) 84 mg QD Mild HI Weak inhibitor of CYP2D6 Ritonavir 45.5 529 (100 mg BID) (31.0, 64.9) (361, 797) 84 mg QD Mild HI Weak inhibitor of CYP3A Fluvoxamine 42.4 482 (300 mg QD) (26.4, 65.9) (281, 850) AUC _0-tau = area under the plasma concentration-time curve from time zero to the end of the dosing interval of 12 hours for BID and 24 hours for QD (AUC _0-tau represents AUC _0-12 for BID and AUC _0-24 for QD mode); BID=twice a day; C _max =maximum observed plasma concentration; QD=once a day.
a: values are given for 3 significant results.

Example 3

An open-label, 2-stage, pharmacokinetic, and single-dose phase 1 tolerability study of eliglustat tartrate in subjects with renal insufficiency (RI) (mild, moderate, and severe) and in subjects with normal renal function comparable to those with RI for age , weight and phenotype of cytochrome P450 [CYP] 2D6 were performed to study the effect of mild, moderate and severe RI on the pharmacokinetics (PK) of eliglustat.

Methodology: open-label, 2-stage, phase 1 pharmacokinetic and tolerability study with the introduction of a single dose of eliglustat tartrate in subjects with renal insufficiency (RI) (mild, moderate and severe) and in subjects with normal renal function, comparable to RI subjects for age, weight and phenotype of cytochrome P450 [CYP] 2D6.

Approximately 32 subjects were planned to be enrolled in phase 2: Phase 1 included 8 subjects with severe RI and 8 subjects with normal renal function who were matched for CYP2D6 phenotype, weight and age. Subjects with mild to moderate RI were recruited in step 2 if the results in subjects with severe RI showed a significant effect of reduced kidney function on the PK of eliglustat compared to corresponding subjects with normal function. Stage 2 was to include 8 subjects with mild and 8 subjects with moderate RI. Each cohort had to include at least 6 CYP2D6 rapid metabolizers (EM). The remaining 2 subjects had to be slow metabolizers (PM), intermediate metabolizers (IM), or EM recruited according to the following precondition: at least 20 subjects had to be screened for each deficient group and recruited no more than 2 PM when they were found . If less than 2 PM were identified, then no more than 2 EM were recruited from a total of 8 subjects. If less than 2 PM and IM were identified, then no more than 2 additional EMs were recruited from a total of 8 subjects. Authorized concomitant medicinal products included no more than one weak CYP3A inhibitor and one weak CYP2D6 inhibitor alone or in combination.

CYP2D6 EMs and IMs were to receive a single dose of 100 mg eliglustat tartrate, while CYP2D6 PMs were to receive a single dose of 50 mg eliglustat tartrate.

Diagnosis and inclusion criteria:

subjects with RI: male (body weight 50.0 to 125.0 kg inclusive) and female (body weight 40.0 to 110.0 kg inclusive) subjects aged 18 to 79 years, with body mass index (BMI ) from 18.0 to 37.0 kg / m2 inclusive, with moderate, moderate or severe RI, determined by creatinine clearance (CrCl), calculated according to the Cockcroft-Gault formula, 50-80 ml / min, 30-50 ml min or <30 ml/min, respectively.

Subjects with normal renal function: male or female subjects aged 18 to 79 years inclusive, body weight within 15% of the corresponding subject's body weight with RI, BMI between 18.0 and 37.0 kg/m ² and CrCl > 80 ml/min. Healthy subjects should also be matched for age and predicted CYP2D6 phenotype based on genotype.

Dosing schedule:

CYP2D6 EM or IM subjects with RI and eligible healthy subjects were given a single dose of 100 mg eliglustat tartrate per capsule (equivalent to 84 mg eliglustat) for administration.

CYP2D6 PM subjects with RI and eligible healthy subjects were given a single dose of 50 mg eliglustat tartrate capsule (equivalent to 42 mg eliglustat) for administration.

Criteria for evaluation:

Pharmacokinetics: Plasma concentrations of eliglustat were used to determine the following PK parameters using non-compartmental methods: maximum observed plasma concentration (C _max ), time to reach C _max (t _max ), area under the plasma concentration versus time curve, calculated using a trapezoidal method from the starting point to the time corresponding to the last measured concentration t _last (AUC _last ), the area under the plasma concentration versus time curve extrapolated to infinity (AUC), the finite half-life associated with the finite slope λz (t _{1 /2Z} ), the apparent total plasma clearance of the drug (CL/F) and the apparent volume of distribution during the final phase (Vz/F).

Sampling times for pharmacokinetic/pharmacodynamic studies and bioanalytical methods:

blood samples were taken to assess plasma concentrations of eliglustat at the following time points: before taking the drug and after 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 36 hours after taking the drug.

Plasma eliglustat concentrations were determined using a validated liquid chromatography technique with tandem mass spectrometry with a lower limit of quantification (LLOQ) of 0.2 ng/mL.

Statistical methods:

pharmacokinetics:

Eliglustat PK parameters were summarized using descriptive statistics for each cohort and for each CYP2D6 phenotype. For log-transformed C _max , AUC _last , AUC, t _1/2z , CL/F, and Vz/F, the effect of severe RI on eliglustat PK parameters after a single dose of eliglustat tartrate was analyzed using a linear fixed effects model for EM subjects. by CYP2D6. Inclusion of the sample, weak inhibitor of CYP3A, age and weight as a covariate was done manually, choosing the model with the lowest AIC value. After testing, the final model was chosen with only one sample as a fixed term. For each parameter from this model, an interval estimate and a 90% confidence interval (CI) of the geometric mean for each sample were determined, as well as for the ratio of geometric means for the severe RI group versus the normal control group.

Safety:

The safety assessment was based on a review of individual values (clinically significant abnormalities) and descriptive statistics (spreadsheets). All safety analyzes were performed using a safety sample and was based on treatment phase data (defined as time from start of study drug administration [IMP] to Day 3 visit). Potentially clinically significant abnormalities (PCSA) of laboratory data, vital signs and ECG data were analyzed using the PCSA list (version 3.0 dated May 24, 2014). Electrocardiogram parameters were obtained by automatic 12-lead ECG reading and analyzed as initial parameter value and change from baseline. Baseline data and changes from baseline in vital signs were summarized using descriptive statistics by sample group and time of measurement. All individual data on biochemistry, hematology and qualitative urine tests were recorded in writing.

Vital signs and ECG parameters were analyzed as initial parameter value and change from baseline.

Adverse events were coded according to the Medical Regulatory Dictionary (MedDRA version 19.1). They were classified into predefined standard categories according to chronological criteria:

pre-treatment adverse events: AE that occurred, progressed (as judged by the investigator), or became severe in the pre-treatment phase (defined as the time interval between signing informed consent and taking the IMP [excluding taking]);

Treatment-Emerged Adverse Events (TEAE): AEs that occurred, progressed, or became severe during the treatment phase;

Post-Treatment Adverse Events: AEs that occurred, progressed, or became severe in the post-treatment phase (defined as the time after the Day 3 visit to completion with EOS).

The number and percentage of subjects with TEAE were recorded by sample group, primary system organ class (SOC), preferred term (PT), and AE diagnosis.

Sample characteristics:

a total of 16 subjects were recruited: 8 subjects were recruited into the severe RI cohort and 8 subjects into the corresponding healthy cohort. In each cohort, 7 subjects were CYP2D6 EM and 1 subject was CYP2D6 IM. Since Stage 1 did not show a significant effect of severe RI on the PK of eliglustat compared to corresponding EMs with normal renal function, a Stage 2 study was not performed. Five EM subjects in the severe RI cohort were concurrently taking a weak CYP3A inhibitor (amlodipine), and 1 IM subject in the severe renal impairment group was taking both a weak CYP2D6 inhibitor (escitalopram) and a weak CYP3A inhibitor (amlodipine). None of the eligible healthy subjects were taking CYP2D6 or CYP3A inhibitors.

Results of a pharmacokinetic study.

Mean ± SD (geometric mean) [CV%] of plasma PK parameters of eliglustat after a single oral dose of 100 mg eliglustat tartrate

Point estimates of geometric mean ratio with 90% CI in EM subjects by CYP2D6

Comparison Parameter Grade 90%CI Severe RI Group vs. Healthy Subjects _Cmax 0.878 (from 0.462 to 1.669) AUC _last 0.994 (from 0.608 to 1.627) AUC 0.986 (from 0.609 to 1.597) t _1/2z 0.776 (from 0.671 to 0.898) CL/F 1.014 (from 0.626 to 1.643) Vz/F 0.787 (from 0.485 to 1.275) Note: Model analysis is log(PK parameter)=sample and is performed on EM patients (7 with severe RI and 7 healthy subjects).

The geometric mean C _max and AUC for eliglustat were similar in subjects with severe RI and in corresponding healthy subjects with the EM CYP2D6 phenotype (0.878 and 0.986 times, respectively). Co-administration of a single weak CYP3A inhibitor (amlodipine) in CYP2D6 EM subjects with severe RI (N=5, geometric mean [CV%] for C _max and AUC: 10.6 ng/mL [46.6] and 98.3 ng.h/mL [45.9] respectively) did not appear to increase eliglustat exposure compared to subjects with severe RI EM receiving eliglustat tartrate alone (N=2, geometric mean [CV%] for _Cmax and AUC: 15.2 ng/ml [12.9] and 104 ng.h/ml [30.3], respectively). Mean t _1/2z values were smaller in subjects with severe RI than in healthy subjects (6.56 vs. 8.50 hours) and t _max values were greater (4.0 vs. 1.5 hours).

It is not possible to draw a definitive conclusion on the effect of RI in CYP2D6 IM because only one CYP2D6 IM with severe RI taking concomitant medications was included. Significantly higher AUC _last values in this subject compared to healthy CYP2D6 IM (6.90-fold) or CYP2D6 healthy EM (32.1-fold) or CYP2D6 EM with severe RI (35. 2 times) are at least partially due to the combined effect of 2 simultaneously administered CYP inhibitors, namely the CYP2D6 inhibitor (escitalopram) and the CYP3A inhibitor (amlodipine).

Security results:

in total, one mild TEAE was observed in 1 subject, and the investigator considered it to be related to the investigational drug: fatigue in a healthy subject. There were no reports of serious adverse events, and there were no cases of death or early termination of participation in the study due to AE. No treatment-induced PCSA was found to be clinically significant in terms of laboratory or vital signs and ECG.

General conclusion:

the impact of mild to moderate hepatic _impairment in a subject was assessed in the single dose Phase 1 study described in Example 1. degree of hepatic insufficiency and 2.81 and 5.16 times in CYP2D6 EMs with moderate hepatic insufficiency compared with healthy CYP2D6 EMs.

Stationary exposures were predicted in CYP2D6 EM with mild to moderate hepatic impairment using the PBPK model. Doses of eliglustat that would result in mean steady state exposures within effective and safe exposure ranges have been proposed for CYP2D6 EM with liver failure when eliglustat is administered alone or with CYP inhibitors. Therefore, rapid CYP2D6 metabolizers with mild hepatic impairment are not recommended to adjust the dosage (i.e. 84 mg twice daily) if eliglustat is administered alone, and if eliglustat is administered with a weak CYP2D6 inhibitor or with strong, moderate or weak CYP3A inhibitor, the dosage of eliglustat is reduced to 84 mg QD. Eliglustat is contraindicated in CYP2D6 rapid metabolizers with moderate hepatic impairment and CYP2D6 rapid metabolizers with mild hepatic impairment when co-administered with a strong or moderate CYP2D6 inhibitor, as steady state mean exposure values were predicted to be significantly higher than the upper limit of effective and safe exposure ranges. Eliglustat is contraindicated in patients with severe hepatic insufficiency due to the possibility of a significant increase in plasma concentrations of eliglustat. As a contraindication for the use of eliglustat, CYP2D6 IM or PM with mild to moderate hepatic impairment is suggested, as steady-state exposure values are not known.

The effect of severe renal impairment was assessed in the single dose phase 1 study described in Example 2. Following a single dose of 84 mg, eliglustat _Cmax and AUC were similar in CYP2D6 EMs with severe renal impairment and healthy CYP2D6 EMs.

Given the lack of an effect on severe renal impairment after single doses, it is assumed that repeated administration of eliglustat EM on CYP2D6 has no effect on the effect of eliglustat, since it is assumed that the time-dependent effect due to the CYP2D6 inhibition mechanism will not depend on renal insufficiency. Therefore, no dose adjustment is suggested for CYP2D6 EM with mild, moderate, or severe RI.

Limited or no data available for EM, IM, or PM for CYP2D6 with end-stage renal disease, and for IM or PM for CYP2D6 with mild, moderate, or severe renal impairment; therefore, eliglustat is not recommended for these patients or should be avoided.

Claims (9)

1. A method for the treatment of Gaucher's disease, which involves administering to a patient in need twice a day a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, where the specified patient is a rapid CYP2D6 metabolizer with mild hepatic insufficiency. 2. A method for the treatment of Gaucher's disease, which involves administering to a patient in need once a day a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, where the specified patient is a rapid CYP2D6 metabolizer with a mild degree of hepatic insufficiency, and where the specified the patient is simultaneously taking a drug that is a weak inhibitor of CYP2D6. 3. A method for the treatment of Gaucher's disease, which involves administering to a patient in need once a day a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, where the specified patient is a rapid CYP2D6 metabolizer with a mild degree of hepatic insufficiency, and where the specified the patient is concomitantly taking a drug that is a strong, moderate, or weak inhibitor of CYP3A. 4. A method for the treatment of Gaucher disease, which involves administering to a patient in need twice a day a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, where the specified patient is a rapid CYP2D6 metabolizer with moderate or severe renal failure. 5. The method according to any one of paragraphs. 1-4, wherein eliglustat, or a pharmaceutically acceptable salt thereof, is eliglustat hemitartrate. 6. The use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, for administration once a day, for the treatment of Gaucher's disease in a patient in need, in combination with a weak inhibitor of CYP2D6, where the specified patient is a rapid CYP2D6 metabolizer and where the said patient has mild hepatic impairment. 7. The use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the main form, for administration once a day, for the treatment of Gaucher's disease in a patient in need, in combination with a strong, moderate or weak inhibitor of CYP3A, wherein said patient is a rapid CYP2D6 metabolizer and wherein said patient has mild hepatic impairment. 8. The use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the basic form, for administration twice a day, for the treatment of Gaucher disease in a patient where the patient is a rapid CYP2D6 metabolizer with mild hepatic insufficiency. 9. Use of a composition containing a dose of 84 mg of eliglustat or its pharmaceutically acceptable salt, in terms of the basic form, for administration twice a day for the treatment of Gaucher disease in a patient where the patient is a rapid CYP2D6 metabolizer with moderate or severe renal insufficiency.

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