Methods for treating gaucher disease

Abstract

To provide methods for treating Gaucher disease in patients with renal or hepatic impairment.SOLUTION: A method of treating Gaucher disease comprises administering to a patient in need thereof an effective amount of eliglustat, or a pharmaceutically acceptable salt thereof, wherein the patient is a CYP2D6 extensive metabolizer with mild hepatic impairment. The effective amount is a twice daily dose of 84 mg of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base a form.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This specification provides a method for treating Gaucher disease in patients with renal or hepatic impairment. [Background technology]

[0002] Sphingoglycolipids (GSLs) are a class of naturally occurring compounds with numerous biological functions, including the ability to promote cell growth, cell differentiation, adhesion between cells or between cells and substrate proteins, binding of microorganisms and viruses to cells, and metastasis of tumor cells. GSLs are derived from glucosylceramide (GlcCer), which is produced from ceramide and UDP-glucose by the enzyme UDP-glucose:N-acylsphingosylcosyltransferase (GlcCer synthase). The structure of ceramide is shown below. [ka]

[0003] GSL accumulation has been linked to several diseases, including Tay-Sachs disease, Gaucher disease, and Fabry disease (see, for example, Patent Document 1). Compounds that inhibit glucosylceramide (GlcCer) synthase can lower GSL levels and have been reported to be useful in treating patients with one of the aforementioned diseases.

[0004] Eliglustat is a glucosylceramide synthase inhibitor currently approved in the United States as the first-line oral therapy for adults with Gaucher disease type 1 (GD1) who have CYP2D6 rapid metabolite (EM), intermediate metabolite (IM), or low metabolite (PM).

[0005] Eliglustat (chemical name: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidine-1-yl)propan-2-yl)octanamide) has the structure of formula (I).

Chem.

[0006] For example, (Patent Document 2) describes the production of the compound of formula (I) and its physical and biological properties.

[0007] Eliglustat is sold in the United States under the trade name Cerdelga (trademark) as the hemitartrate of formula (Ia),

Chem.

[0008] The production of eliglustat tartrate is described, for example, in (Patent Document 3).

[0009] The use of eliglustat or a pharmaceutically acceptable salt thereof for treating patients who are CYP2D6 rapid metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM) is described in (Patent Document 3).

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

[0012] Accordingly, the present invention provides a method for treating Gaucher disease, comprising administering an effective dose of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is a CYP2D6 rapid metabolite (Child-Pewcras A cirrhosis) with mild hepatic impairment. In one embodiment, the effective dose is 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form, in a twice-daily dose. In one embodiment, Gaucher disease is Gaucher disease type 1.

[0013] In another embodiment, the present invention provides a method for treating Gaucher disease, comprising administering a modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is a CYP2D6 rapid metabolite with mild hepatic impairment and is concurrently taking a drug that is a weak CYP2D6 inhibitor. In one aspect of this embodiment, the modified effective dose is 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form, once daily. In one aspect, Gaucher disease is Gaucher disease type 1.

[0014] In another embodiment, the present invention provides a method for treating Gaucher disease, comprising administering a modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is a CYP2D6 rapid metabolite with mild hepatic impairment, and the patient is concurrently taking a drug that is a potent, moderate, or weak CYP3A inhibitor. In one aspect of this embodiment, the modified effective dose is 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form, once daily. In one aspect, Gaucher disease is Gaucher disease type 1.

[0015] In another embodiment, the present invention provides a method for treating Gaucher disease, comprising administering an effective dose of eliglustat or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient is a CYP2D6 rapid metabolite with mild, moderate, or severe renal impairment. In one aspect of this embodiment, the effective dose is 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form, in a twice-daily dose. In one aspect, Gaucher disease is Gaucher disease type 1. [Brief explanation of the drawing]

[0016] [Figure 1] This figure shows the individual C-values ​​after a single dose of 84 mg of eliglustat, as demonstrated in the study conducted in Example 1. [Figure 2] This figure shows the individual AUC values ​​after a single dose of eliglustat 84 mg, as performed in the study conducted in Example 1. [Figure 3] This figure shows the eliglustat concentration-time profile (mean ± SD) in the functional impairment group after a single 84 mg dose of eliglustat, as performed in the study conducted in Example 1 (linear-linear scale). [Figure 4] This figure (log-linear scale) shows the eliglustat concentration-time profile (mean ± SD) in the functional impairment group after a single 84 mg dose of eliglustat, as performed in the study conducted in Example 1. [Figure 5]This figure shows the individual C-values ​​after a single dose of 84 mg of eliglustat, as demonstrated in the study conducted in Example 3. [Figure 6] This figure shows the individual AUC values ​​after a single dose of 84 mg of eliglustat, as demonstrated in the study conducted in Example 3. [Modes for carrying out the invention]

[0017] The following terms, used above and throughout this description of the present invention, shall not be defined unless otherwise specified. It is understood to have the following meanings:

[0018] As used herein, “simultaneously administered,” “to administer simultaneously,” “in combination,” and “taken at the same time” mean administered or taken simultaneously, on the same day, or within a 24-hour period, particularly within a 12-hour period.

[0019] As used herein, “effective dose” means the amount of eliglustat that would be recommended for a patient to take, or that a physician would prescribe for a patient to take, provided the patient does not have hepatic or renal impairment. In one embodiment, the effective dose of eliglustat is the amount approved by the U.S. Food and Drug Administration, which is 84 mg twice daily for patients with CYP2D6 EM or IM, and 84 mg once daily for patients with PM. The dose of eliglustat is calculated based on its free base form. Eliglustat may be administered as a pharmaceutically acceptable salt, in particular as hemi-tartrate, and it will be understood that the amount of salt administered should be adjusted accordingly.

[0020] As used in this specification, "patient" means a human being.

[0021] As used herein, “pharmaceutically acceptable salt” means that a salt of the compound of the present invention can be used in the manufacture of pharmaceuticals.

[0022] The expression "compound for use in ~" as used herein will be understood to be equivalent to, for example, the expression "use of a compound for ~" or "use of a compound for manufacturing a pharmaceutical for use in ~".

[0023] In certain embodiments, a patient's liver function is assessed using the Child-Pugh classification system, which defines three classes of cirrhosis. This system assigns points to one of five measures: total bilirubin level, serum albumin level, prothrombin time, ascites, and hepatic encephalopathy. Each measure is given a rank of 1, 2, or 3, and the sum of the five ranks is the Child-Pugh score. The Child-Pugh score is used to classify liver impairment by placing the patient in a Child-Pugh class of Child-Pugh class A (mild liver impairment), Child-Pugh class B (moderate liver impairment), and Child-Pugh class C (severe liver impairment).

[0024] In certain embodiments, a patient's renal function is determined by creatinine clearance calculated by the Cockcroft-Gault formula, where subjects or patients with a creatinine clearance >80 mL / min have normal renal function, subjects or patients with a creatinine clearance of 50-80 mL / min have mild renal impairment, subjects or patients with a creatinine clearance of 30-50 mL / min have moderate renal impairment, and subjects or patients with a creatinine clearance <30 mL / min have severe renal impairment.

[0025] Eliglustat is metabolized by the liver, primarily by cytochrome P450 enzymes. Cytochrome P450 ("CYP") are the major hepatic xenobiotic metabolic enzymes. There are 11 xenobiotic cytochrome P450 isoforms expressed in a typical 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 main cytochrome P450 isoforms responsible for the metabolism of eliglustat and its pharmaceutically active salt, eliglustat tartrate. The activity levels of some P450 enzymes, such as CYP2D6, vary depending on the individual CYP2D6 phenotype. It varies accordingly. For example, individuals can be classified as having low, intermediate, rapid, and hyperfast CYP2D6 metabolites.

[0026] Patients are typically assessed by genotyping as having low, intermediate, rapid, or hyperfast CYP2D6 metabolism, but rarely, genotyping is not possible (undeterministic metabolism).

[0027] For example, a patient may have a low P450 metabolite as a result of 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, that is, by genotyping the patient for the P450 enzyme. For example, CYP2D6 expression is commonly assessed by 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 pharmacogenomics testing based on microarrays. Therefore, a patient can be conveniently genotyped for P450 expression (e.g., CYP2D6) before initiating treatment, and an effective dose adjusted as needed can be administered.

[0028] The CYP2D6 gene has four predicted phenotypes.

[0029] The term "CYP2D6 low metabolite" as used herein refers to a gene possessing two mutant alleles, which result in a complete loss of enzyme activity.

[0030] As used herein, the "CYP2D6 intermediate metabolite" possesses one reduced-activity allele and one null allele.

[0031] As used herein, "CYP2D6 rapid metabolite" refers to a gene possessing at least one and no more than two normal functional alleles.

[0032] The "CYP2D6 hyperfast metabolite" as used herein possesses multiple copies (3 to 13) of functional alleles, resulting in excessive enzyme activity.

[0033] Since eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A, co-administration with certain drugs that are CYP2D6 enzyme inhibitors may increase eliglustat concentrations in patients. Examples of weak CYP2D6 inhibitors include, but are not limited to, esitalopram, abiraterone, diphenhydramine, amiodarone, delamicran, desvenlafaxine, fosdevine, daclatasvir / asunaprevir / beclabuvir, oral contraceptives, oscillodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, celecoxib, felodipine, fluvoxamine, gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, esitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir / ritonavir, sarpogrelate, artesunate / pyronarizine, imatinib, and febuxostat. Examples of moderate CYP2D6 inhibitors include, but are not limited to, duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, doronedarone, lorapitant, cimetidine, and tipranavir / ritonavir. Examples of potent CYP2D6 inhibitors include, but are not limited to, paroxetine, fluoxetine, quinidine, bupropion, and dacomitinib.

[0034] Patients with a low metabolic rate of CYP2D6 have little to no CYP2D6 function, or Because they lack the necessary enzymes, eliglustat metabolism in these patients is primarily via the CYP3A pathway. Eliglustat metabolism in these patients may be further impaired as a result of treatment with certain drugs that are CYP3A enzyme inhibitors. Examples of weak CYP3A inhibitors, but not limited to them, include amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and lanolazine. Examples of moderate CYP3A inhibitors include, but are not limited to, erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine, amprenavir, casopitant, crizotinib, faldaprevir, ledipasvir, netupitant, nilotinib, tofisopam, doronedarone, cimetidine, and cyclosporine. Examples of potent CYP3A inhibitors include, but are not limited to, ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir, idelalisib, mibeflazil, nefazodone, nelfinavir, elvitegravir / ritonavir, danopravir / ritonavir, and troleandomycin.

[0035] Another embodiment provided herein is a method for providing eliglustat or a pharmaceutically acceptable salt thereof, with information indicating that it is useful for the treatment of patients with Gaucher disease, particularly adult patients with Gaucher disease type 1, and that no dose adjustment is necessary if the patient is a CYP2D6 rapid metabolite with mild hepatic impairment. In one aspect of this embodiment, the recommended or effective dose is 84 mg of eliglustat, measured as a base, twice daily.

[0036] Another embodiment provided herein is a method for providing eliglustat or a pharmaceutically acceptable salt thereof, with information indicating that it is useful for the treatment of patients with Gaucher disease, particularly adult patients with Gaucher disease type 1, and that the effective dose should be reduced to an adjusted effective dose if the patient is a CYP2D6 rapid metabolizer with mild hepatic impairment and is co-administered with a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor. In one aspect of this embodiment, the adjusted effective dose is 84 mg of eliglustat, measured as base, once daily.

[0037] Another embodiment provided herein is a method for providing eliglustat or a pharmaceutically acceptable salt thereof, wherein the eliglustat or a pharmaceutically acceptable salt thereof is provided with information indicating that it is contraindicated in CYP2D6 IM or PM with any degree of hepatic impairment, and in CYP2D6 EM with moderate or severe hepatic impairment.

[0038] Another embodiment provided herein is a method for providing eliglustat or a pharmaceutically acceptable salt thereof, with information indicating that it is useful for the treatment of patients with Gaucher disease, particularly adult patients with Gaucher disease type 1, and that no dose adjustment is necessary if the patient is a CYP2D6 rapid metabolite with mild, moderate, or severe renal impairment. In one aspect of this embodiment, the recommended or effective dose is 84 mg of eliglustat, measured as a base, twice daily.

[0039] Another embodiment provided herein is a method for providing eliglustat or a pharmaceutically acceptable salt thereof, wherein eliglustat or a pharmaceutically acceptable salt thereof Eliglustat or its pharmaceutically acceptable salts are used in CYP2D6 patients with end-stage renal disease. The method is provided along with information indicating that it is not recommended or should be avoided in EM and CYP2D6 IM or PM with mild, moderate, or severe renal impairment or end-stage renal disease.

[0040] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) Labels or accompanying documents contained within the packaging material indicating that eliglustat or pharmaceutically acceptable salts thereof are contraindicated in CYP2D6 intermediate metabolite (IM) or hypometabolite (PM) with any degree of hepatic impairment, and in CYP2D6 rapid metabolite (EM) with moderate or severe hepatic impairment. The product includes the above.

[0041] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) A label or accompanying leaflet contained within the packaging material indicating that dose adjustment of eliglustat or a pharmaceutically acceptable salt thereof is not necessary in CYP2D6 rapid metabolite (EM) with mild hepatic impairment. The product includes the above.

[0042] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) Eliglustat or pharmaceutically acceptable salts thereof are contraindicated in rapid metabolite (EM) patients with mild hepatic impairment taking potent or moderate CYP2D6 inhibitors; and in CYP2D6 rapid metabolite (EM) patients with mild hepatic impairment taking weak CYP2D6 inhibitors or potent, moderate, or weak CYP3A inhibitors, a dose of 84 mg of eliglustat once daily should be considered, as indicated by the label or accompanying leaflet contained within the packaging material. The product includes the above.

[0043] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) A label or accompanying leaflet contained within the packaging material indicating that dose adjustment of eliglustat or a pharmaceutically acceptable salt thereof is not necessary in CYP2D6 rapid metabolites with mild, moderate, or severe renal impairment. The product includes the above.

[0044] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) Labels or accompanying documents contained within the packaging materials indicating that eliglustat or any pharmaceutically acceptable salt thereof is not recommended or should be avoided in CYP2D6 rapid metabolite (EM) patients with end-stage renal disease. The product includes the above.

[0045] Another embodiment provided herein is a product, a) Packaging materials and; b) with eliglustat or a pharmaceutically acceptable salt thereof; c) Labels or accompanying documents contained within the packaging materials indicating that eliglustat or pharmaceutically acceptable salts thereof should be avoided in intermediate-metabolite (IM) or low-metabolite (PM) individuals with mild, moderate, or severe renal impairment or end-stage renal disease. The product includes the above.

[0046] Another embodiment provided herein is a package comprising eliglustat or a pharmaceutically acceptable salt thereof and a label, wherein the label includes printed statements informing the intended user that eliglustat or a pharmaceutically acceptable salt thereof is i) indicated for the treatment of Gaucher disease type 1 and ii) contraindicated in CYP2D6 intermediate metabolite (IM) or hypometabolite (PM) with any degree of hepatic impairment, and CYP2D6 rapid metabolite (EM) with moderate or severe hepatic impairment.

[0047] Another embodiment provided herein is a package comprising eliglustat or a pharmaceutically acceptable salt thereof and a label, wherein the label includes printed statements informing the intended user that eliglustat or a pharmaceutically acceptable salt thereof is i) indicated for the treatment of Gaucher disease type 1 and ii) contraindicated in rapid metabolites (EMs) with mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor. For CYP2D6 rapid metabolites (EMs) with mild hepatic impairment taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor, a dose of 84 mg of eliglustat once daily should be considered.

[0048] Another embodiment provided herein is a package comprising eliglustat or a pharmaceutically acceptable salt thereof and a label, wherein the label includes printed statements informing the intended user that eliglustat or a pharmaceutically acceptable salt thereof is i) indicated for the treatment of Gaucher disease type 1 and ii) not recommended or should be avoided in CYP2D6 rapid metabolite (EM) with end-stage renal disease (ESRD).

[0049] Another embodiment provided herein is a package comprising eliglustat or a pharmaceutically acceptable salt thereof and a label, wherein the label includes printed statements informing the intended user that eliglustat or a pharmaceutically acceptable salt thereof is indicated for the treatment of Gaucher disease type 1, and that it is not recommended for intermediate metabolites (IM) or hypometabolites (PM) with mild, moderate, or severe renal impairment or end-stage renal disease, and that eliglustat is not recommended or should be avoided for CYP2D6 rapid metabolites (EM) with end-stage renal disease.

[0050] Another embodiment provided herein is a method for treating Gaucher disease, comprising administering a modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof in combination with a weak CYP2D6 inhibitor to a patient in need thereof, wherein the patient is CYP2D6 rapidly metabolized and has mild hepatic impairment. In one aspect of this embodiment, the modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof is a dose of 84 mg of eliglustat, measured in nucleotide form, once daily. In another aspect, the weak CYP2D6 inhibitor is esitalopram, abiraterone, diphenhydramine, amiodarone, delamcyclane, desvenlafaxine, fosdevine, daclatasvir / asunaprevir / beclabuvir, oral contraceptives, oscillodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, celecoxib, These include felodipine, fluvoxamine, gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, esitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir / ritonavir, sarpogrelate, artesunate / pyronalizine, imatinib, or febuxostat. In another embodiment, Gaucher disease is Gaucher disease type 1.

[0051] Another embodiment provided herein is a method for treating Gaucher disease, comprising administering a modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof in combination with a potent, moderate, or weak CYP3A inhibitor to a patient in need thereof, wherein the patient is CYP2D6 rapidly metabolized and has mild hepatic impairment. In one aspect of this embodiment, the modified effective dose of eliglustat or a pharmaceutically acceptable salt thereof is a dose of 84 mg of eliglustat, measured in nucleotide form, once daily. Examples of weak CYP3A inhibitors include amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and lanolazine. In one embodiment, the moderate 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, netupitant, nilotinib, tofisopam, doronedarone, cimetidine, and cyclosporine. In one embodiment, the potent CYP3A inhibitor is selected from the group consisting of 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. In another embodiment, Gaucher disease is Gaucher disease type 1.

[0052] In another embodiment, the present invention provides eliglustat or a pharmaceutically acceptable salt thereof for use in the treatment of Gaucher disease in a patient, wherein the patient is a CYP2D6 rapid metabolite with mild hepatic impairment. In one embodiment, eliglustat or a pharmaceutically acceptable salt thereof is administered in an effective dose, which is 84 mg measured in base form, twice daily. In another embodiment, Gaucher disease is Gaucher disease type 1.

[0053] In another embodiment, the present invention provides eliglustat or a pharmaceutically acceptable salt thereof for use in the treatment of Gaucher disease in a patient, wherein the patient is a CYP2D6 rapid metabolite with mild hepatic impairment and is concurrently taking a drug that is a weak CYP2D6 inhibitor. In one embodiment, eliglustat or a pharmaceutically acceptable salt thereof is administered in a modified effective dose, which is a once-daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in base form. In another embodiment, weak CYP2D6 inhibitors are selected from esitalopram, abiraterone, diphenhydramine, amiodarone, delamicran, desvenlafaxine, fosdevine, daclatasvir / asunaprevir / beclabuvir, oral contraceptives, oscillodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, celecoxib, felodipine, fluvoxamine, gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, esitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir / ritonavir, sarpogrelate, artesunate / pyronarizine, imatinib, and febuxostat. In another aspect, Gaucher disease is Gaucher disease type 1.

[0054] In another embodiment, the present invention provides eliglustat or a pharmaceutically acceptable salt thereof for use in the treatment of Gaucher disease in a patient, wherein the patient is a CYP2D6 rapid metabolite with mild hepatic impairment, and the patient is concurrently taking a drug that is a potent, moderate, or weak CYP3A inhibitor. In one aspect of this embodiment, eliglustat or a pharmaceutically acceptable salt thereof is administered in a regulated effective dose, the regulated effective dose being 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in base form, once daily. In one aspect, the weak CYP3A inhibitor is selected from, for example, amlodipine, cilostazol, fluvoxamine, hydrastis, isoniazid, ranitidine, and lanolazine. In one embodiment, a moderate CYP3A inhibitor is selected from the group consisting of, for example, erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, and cimetidine. In another embodiment, a potent CYP3A inhibitor is selected from the group consisting of, for example, ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, and boceprevir. In yet another embodiment, Gaucher disease is Gaucher disease type 1.

[0055] In another embodiment, the present invention provides eliglustat or a pharmaceutically acceptable salt thereof for use in the treatment of Gaucher disease in a patient, the patient being a CYP2D6 rapid metabolite 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 dose, which is 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in base form, twice daily. In another embodiment, Gaucher disease is Gaucher disease type 1.

[0056] For its therapeutic use, eliglustat and its pharmaceutically acceptable salts are commonly incorporated into pharmaceutical compositions.

[0057] These pharmaceutical compositions comprise eliglustat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0058] The excipient is selected from common excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.

[0059] For example, a dose of eliglustat in capsule form or a pharmaceutically acceptable salt thereof may correspond to the following example: a capsule for oral use containing 84 mg of eliglustat (equivalent to 100 mg of hemi tartrate), microcrystalline cellulose, lactose monohydrate, hypermellose, and glyceryl behenate.

[0060] The present invention can be better understood by referring to the following non-limiting embodiments illustrating the invention. However, this should not be construed as limiting the scope of the invention in any way. [Examples]

[0061] A multicenter, open-label, single-dose study of eliglustat tartrate administered to weight- and cytochrome P450 [CYP]2D6 phenotype-matched subjects with mild or moderate hepatic impairment (HI) and normal liver function (healthy) was conducted to investigate the effects of mild and moderate hepatic impairment (HI) on the pharmacokinetics (PK) of eliglustat.

[0062] Approximately eight subjects were planned to be enrolled in their respective HI groups (mild or moderate HI), as well as eight subjects with normal liver function who were matched to subjects with impaired weight and CYP2D6 phenotype. At least six CYP2D6 rapid metabolites (EMs) were enrolled in their respective impairment groups, and the remaining two subjects were enrolled in the following priority order: At least 20 subjects were screened for each impairment group, and if identified, up to two CYP2D6 low metabolites (PMs) were enrolled. If fewer than two PMs were identified, up to two CYP2D6 intermediate metabolites (IMs) were enrolled, bringing the total to eight subjects per group. If fewer than two PMs or IMs were identified, up to two additional EMs were enrolled, bringing the total to eight subjects per group. If two PMs were identified before screening 20 subjects, the screening could be stopped. If the above requirements were met and a suitable PM subject was identified after eight subjects had been enrolled in one disability group, that subject could still be enrolled in that disability group.

[0063] CYP2D6 EM and IM were given a single 100 mg dose of eliglustat tartrate, while CYP2D6 PM was given a single 50 mg dose of eliglustat tartrate.

[0064] Inclusion diagnosis and criteria: HI target group: 18-79 years old (comprehensive), weight index 18.0-37 kg / m² 2 Male (weight 50.0–125.0 kg (inclusive)) or female (weight 40.0–110.0 kg (inclusive)) subjects (inclusive); having stable chronic liver disease as assessed by medical history, physical examination, and laboratory values; having moderate HI (defined as a Child-Puer score of 7–9 (inclusive)) or mild HI (defined as a Child-Puer score of 5–6 (inclusive)).

[0065] Healthy subjects: Male or female subjects aged 18-79 years (inclusive); with a weight no more than 15% of the weight of a matched subject with HI, and a weight index of 18.0-37 kg / m². 2(Included); Healthy subjects were also matched to the HI group based on the CYP2D6 phenotype predicted from the genotype.

[0066] Dosing Regimen: A single 100 mg capsule of eliglustat tartrate (equivalent to 84 mg of eliglustat) was administered to CYP2D6 EM or IM subjects with mild or moderate HI and matched healthy subjects.

[0067] A single 50 mg capsule of eliglustat tartrate (equivalent to 42 mg of eliglustat) was administered to CYP2D6 PM subjects with mild or moderate HI and matched healthy subjects.

[0068] Evaluation Criteria: Pharmacokinetics: Using the non-compartmental method, the following PK parameters were calculated for eliglustat plasma concentrations: observed maximum plasma concentration (C 最大 ), time t corresponding to the last quantifiable concentration from time zero to AUC 最後 calculated using the trapezoidal method from the plasma concentration-time curve, AUC 最後 ), time to reach C 最大 (t 最大 ), area under the plasma concentration-time curve extrapolated to infinity (AUC), terminal half-life (t 1 / 2z ) related to the terminal slope λz, time corresponding to the last concentration above the limit of quantification (t 最後 ), apparent total body clearance of the drug from plasma (CL / F), and apparent volume of distribution during the terminal (λz) phase (Vz / F).

[0069] Pharmacokinetic Sampling Times and Biological Analytical Methods: Blood samples were collected at the following time points to evaluate the plasma concentration of eliglustat: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours post-dose.

[0070] Eliglustat concentrations in plasma were determined using a validated liquid chromatography-tandem mass spectrometry method with a limit of quantification of 0.2 ng / mL.

[0071] Statistical method: Pharmacokinetics Eliglustat PK parameters were aggregated using descriptive statistics for each population and each CYP2D6 phenotype. Logarithmically transformed C 最大 AUC 最後 , AUC, t 1 / 2z For CL / F and Vz / F, the effect of single-dose eliglustat tartrate on hepatic impairment of eliglustat PK parameters was analyzed using a linear fixed-effects model targeting CYP2D6 EM. Estimates of the geometric mean of each population group and the geometric mean ratio of the impaired liver group versus the normal control group, along with 90% confidence intervals (CIs), are provided for each parameter.

[0072] safety Safety assessments were based on a review of individual values ​​(clinically significant abnormalities) and descriptive statistics (aggregate tables). All safety analyses were performed using a safe population and based on the intermediate stage of treatment (defined as the time from administration of the drug product under study [IMP] to the 3-day visit (comprehensive)). In the laboratory, vital signs and ECG data, clinically significant potential abnormalities (PCSAs) were analyzed using the May 24, 2014 version of the PCSA list. ECG parameters were obtained from automated readings of 12-lead ECGs and analyzed as raw parameter values ​​and changes from baseline. For vital signs, raw data and changes from baseline were aggregated using descriptive statistics by population and time. All individual data from biochemistry, hematology, and qualitative urinalysis were enumerated.

[0073] Adverse events were coded according to the International Medical Terminology Dictionary (MedDRA v.19.1) and classified into predefined standard classifications according to time-series criteria: • A pre-treatment adverse event (AE) is defined as an AE that occurred, worsened (at the investigator's discretion), or became serious during the pre-treatment phase (defined exclusively as the time between signing informed consent and administration of IMP); • Defined as an adverse event (TEAE) caused by the procedure, or an adverse event that occurred, worsened, or became severe during the course of the procedure; • Post-treatment AEs are defined as AEs that occur, worsen, or become serious during the post-treatment phase (defined as the time from the third-day visit until the completion of End-of-Services).

[0074] All adverse events (AEs) reported during the study were listed and arranged in order of subject and onset date.

[0075] The number and percentage of subjects with TEAEs were listed by population group, organ-specific classification (SOC), basic term (PT), and AE diagnosis.

[0076] Group characteristics: Eight subjects were enrolled in separate groups. Seven CYP2D6 EMs and one CYP2D6 IM were enrolled in the moderate impairment group and the healthy matched group, respectively, while six CYP2D6 EMs and two CYP2D6 IMs were enrolled in the mild impairment group.

[0077] Pharmacokinetic results: Mean ± SD (geometric mean) [CV%] Single dose elimination in CYP2D6 EM subjects PK parameters of eliglustat after 100 mg of lustat tartrate

[0078] [Table 1]

[0079] [Table 2]

[0080] Compared to healthy CYP2D6 EM, after a single 100 mg dose of eliglustat tartrate, the mean C15 of eliglustat increased. 最大 The AUC was slightly higher in CYP2D6 EM with mild HI (1.22 and 1.15 times, respectively) and considerably higher in subjects with moderate HI (2.81 and 5.16 times, respectively). 1 / 2z The values ​​were similar in subjects with mild HI and healthy subjects, but were prolonged in subjects with moderate HI (10.5 hours vs. 7.08 hours).

[0081] Safety results: A total of six mild TEAEs were observed in five subjects. Four TEAEs in three subjects were considered by investigators to be related to the study drug: dysgeusia in two subjects with moderate HI and nausea and headache in one healthy subject. No serious adverse events were reported, and there were no deaths or other significant AEs. There were no clinically relevant, procedure-induced PCSAs in terms of laboratory values, vital signs, or ECG. [Examples]

[0082] Using observed single-dose data from both healthy and hepatic impaired patients in the study described in Example 1, a physiological pharmacokinetic (PBPK) model developed using preclinical and clinical study results of eliglustat was validated. This PBPK model was used to predict eliglustat exposure after repeated dosing in CYP2D6 EM subjects with mild and moderate HI, as well as in a comparison group of healthy CYP2D6 EM subjects (without HI). Eliglustat PK simulations were performed using 10 virtual trials of 10 subjects / classifications, after repeated dosing of 84 mg of eliglustat orally twice daily (BID) or once daily (QD) for 8 days, and the simulation results are presented in Table 1.

[0083] [Table 3]

[0084] To ensure that eliglustat exposure remains within the range of eliglustat exposure demonstrated to be safe and effective in clinical development programs, eliglustat 84 mg QD, when co-administered with a CYP2D6 inhibitor or a CYP3A inhibitor, was evaluated using PBMK modeling for CYP2D6 EM with mild HI. Various scenarios of co-administration of eliglustat 84 mg QD with a CYP2D6 inhibitor or a CYP3A inhibitor were simulated using Simcyp built-in models of the inhibitors, with minor modifications as needed. Paroxetine, terbinafine, and ritonavir were used as potent, moderate, and weak CYP2D6 inhibitors, respectively, while ketoconazole, fluconazole, and fluvoxamine were used as potent, moderate, and weak CYP3A inhibitors, respectively. Simulations of eliglustat PK were performed using 10 virtual trials involving 10 CYP2D6 EMs with mild HI, after repeated administrations of 84 mg QD eliglustat alone for 8 days (days 1 to 8), and then with a CYP2D6 or CYP3A inhibitor for an additional 7 or 10 days (days 9 to 15 or 9 to 18). Table 2 shows the predicted mean eliglustat exposure (range of the mean from the 10 virtual trials) in CYP2D6 EMs with mild HI when eliglustat was administered concurrently with a CYP2D6 or CYP3A inhibitor. Simulated exposures in healthy EMs and EMs with mild HI after 84 mg BID of eliglustat alone are also included for comparison.

[0085] [Table 4] [Examples]

[0086] A phase 1, open-label, two-step pharmacokinetic and tolerable study of single-dose eliglustat tartrate was conducted in subjects with mild, moderate, and severe renal impairment (RI), as well as in subjects with normal renal function matched for age, weight, and cytochrome P450 [CYP]2D6 phenotype to RI subjects, to investigate the effects of mild, moderate, and severe RI on the pharmacokinetics (PK) of eliglustat.

[0087] Methods: A phase 1, open-label, two-step pharmacokinetic and tolerable study of single-dose eliglustat tartrate in subjects with renal impairment (RI) (mild, moderate, and severe), as well as in subjects with normal renal function matched for age, weight, and cytochrome P450 [CYP]2D6 phenotype to the RI subjects.

[0088] Approximately 32 subjects were scheduled to be enrolled in two stages: Stage 1 consisted of 8 subjects with severe radioisotopes (RI) and 8 subjects with normal renal function, matched for CYP2D6 phenotype, weight, and age. Subjects with mild and moderate RI were enrolled in Stage 2 if the results in subjects with severe RI showed a substantial effect of reduced renal function on eliglustat PK compared to matched subjects with normal function. Stage 2 included 8 subjects with mild RI and 8 subjects with moderate RI. Each cohort enrolled at least 6 subjects with rapid CYP2D6 metabolic (EM). The remaining 2 subjects were either low-metabolic (PM), intermediate-metabolic (IM), or EM, and were enrolled in the following priority order: at least 20 subjects were screened for each cohort, and if identified, up to 2 PMs were enrolled. If fewer than 2 PMs were identified, up to 2 IMs were enrolled, resulting in a total of 8 subjects. If fewer than two PMs and IMs were identified, up to two additional EMs were enrolled to bring the total number of subjects to eight. Acceptable concomitant medications included only one or fewer weak CYP3A inhibitors and one or fewer weak CYP2D6 inhibitors, either alone or in combination.

[0089] CYP2D6 EM and IM were given a single 100 mg dose of eliglustat tartrate, while CYP2D6 PM was given a single 50 mg dose of eliglustat tartrate.

[0090] Inclusion diagnosis and criteria: RI eligibility: Males (weight 50.0–125.0 kg (inclusive)) and females (weight 40.0–110.0 kg (inclusive)) aged 18–79 years with a body mass index (BMI) of 18.0–37.0 kg / m2 (inclusive), having mild, moderate, or severe RIs determined by creatinine clearance (CrCl) and calculated using the Cockcroft-Gault formula, with flow rates of 50–80 mL / min, 30–50 mL / min, or <30 mL / min, respectively.

[0091] Eligibility criteria for normal renal function: Male or female subjects, 18-79 years old (inclusive), weight within 15% of the weight of matched subjects with radioisotopes, BMI 18.0-37.0 kg / m². 2 , and CrCl >80 mL / min. Healthy subjects were also matched by predictive CYP2D6 phenotype based on age and genotype.

[0092] Dosage regimen: A single 100 mg capsule of eliglustat tartrate (equivalent to 84 mg of eliglustat) was administered to CYP2D6 EM or IM subjects with radioisotopes and matched healthy subjects.

[0093] A single 50 mg capsule of eliglustat tartrate (equivalent to 42 mg of eliglustat) was administered to CYP2D6 PM subjects with radioisotopes and matched healthy subjects.

[0094] Evaluation criteria: Pharmacokinetics: Using a non-compartmentalization method, the following PK parameters were determined using plasma eliglustat concentrations: observed maximum plasma concentration (C 最大 ), C 最大 The first time it reached (t 最大 ), time t corresponding to the last concentration above the limit of quantification from time zero.最後 Area under the plasma concentration-time curve (AUC) calculated using the trapezoidal rule. 最後 ), area under the plasma concentration-time curve extrapolated to infinity (AUC), terminal half-life (t) related to terminal slope λz 1 / 2z ), The apparent systemic clearance (CL / F) of a drug from plasma, and the apparent volume of its distribution during the terminal stage (VZ / F).

[0095] Pharmacokinetics / pharmacodynamics: Sampling time and biological analytical methods: Blood samples were collected at the following time points to evaluate the plasma concentration of eliglustat: before administration, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 36 hours after administration.

[0096] Eliglustat concentrations in plasma were determined using a validated liquid chromatography-tandem mass spectrometry method with a limit of quantification (LLOQ) of 0.2 ng / mL.

[0097] Statistical method: Pharmacokinetics: Eliglustat PK parameters were aggregated using descriptive statistics for each population and each CYP2D6 phenotype. Logarithmically transformed C 最大 AUC 最後 , AUC, t 1 / 2z For CL / F and Vz / F, the effect of severe RI on eliglustat PK parameters after single-dose eliglustat tartrate was analyzed using a linear fixed-effects model for CYP2D6 EM subjects. Inclusion of population, weak CYP3A inhibitors, age, and weight as covariates was manually selected, and the model with the lowest AIC value was chosen. After the trial, the final model selected had only population as a definitive condition. Estimates of the geometric mean of each population group and the geometric mean ratio of severe RI group versus normal control group, along with 90% confidence intervals (CI), were provided from this model for each parameter.

[0098] Safety: Safety assessments were based on a review of individual values ​​(clinically significant abnormalities) and descriptive statistics (aggregate tables). All safety analyses were performed using a safety population and were based on the intermediate stage (defined as the visit from the start of administration of the drug product under study [IMP] to day 3). In the laboratory, vital signs and ECG data, and potentially clinically significant abnormalities (PCSAs) were analyzed using the PCSA list (version 3.0, May 24, 2014). ECG parameters were obtained from automated readings of 12-lead ECGs and analyzed as raw parameter values ​​and changes from baseline. For vital signs, raw data and changes from baseline were aggregated using descriptive statistics by population and measurement time. All individual data from biochemistry, hematology, and qualitative urinalysis were enumerated.

[0099] Vital signs and ECG readings were analyzed as bioparameter values ​​and changes from baseline.

[0100] Adverse events were coded according to the International Medical Terminology Dictionary (MedDRA, version 19.1). These were then classified into predefined standard classifications according to chronological criteria: • Pre-treatment adverse events: AEs that occurred, worsened (as determined by the investigator), or became serious during the pre-treatment phase (defined exclusively as the time between signing informed consent and administration of IMP); • Treatment-related adverse events (TEAEs): Adverse events that occurred, worsened, or became serious during the course of treatment; • Post-treatment adverse events: AEs that occur, worsen, or become serious during the post-treatment phase (defined as starting after the 3rd day visit and ending with EOS).

[0101] The number and percentage of subjects with TEAEs were listed by population group, organ-specific classification (SOC), basic term (PT), and AE diagnosis.

[0102] Group characteristics: A total of 16 subjects were enrolled: 8 were enrolled in the severe renal impairment cohort and 8 in the healthy matched cohort. In each cohort, 7 subjects were CYP2D6 EM and 1 subject was CYP2D6 IM. In Phase 1, Phase 2 of the study was not performed because no substantial effect of severe RI compared to eliglustat PK was demonstrated in EM compared to matched normal renal function. Five EM subjects in the severe RI cohort were concurrently taking a weak CYP3A inhibitor (amlodipine), and one IM subject in the severe renal impairment cohort was concurrently taking both a weak CYP2D6 inhibitor (esitalopram) and a weak CYP3A inhibitor (amlodipine). None of the healthy matched subjects were taking CYP2D6 or CYP3A inhibitors.

[0103] [Table 5]

[0104] [Table 6]

[0105] Eliglustat's geometric mean C 最大 The AUC values ​​were similar in subjects with the CYP2D6 EM phenotype, severe RIs, and healthy matched subjects (0.878 and 0.986 times, respectively). Concurrent administration of a single weak CYP3A inhibitor (amlodipine) in CYP2D6 EM subjects with severe RIs (N=5, C 最大 The geometric mean [CV%] of AUC (10.6 ng / mL [46.6] and 98.3 ng.h / mL [45.9], respectively) did not appear to result in increased eliglustat exposure compared to EM subjects with severe RI who were given eliglustat tartrate alone (N=2, C 最大 Geometric mean [CV%] of AUC: 15.2 ng / mL [12.9] and 104 ng.h / mL [30.3], respectively. Mean t of severe RI subjects 1 / 2zThe values ​​were shorter than in healthy subjects (6.56 vs. 8.50 hours), t 最大 The value was longer (4.0 vs. 1.5 hours).

[0106] Since only one CYP2D6 IM patient with a serious radioisotope (RI) condition and taking concomitant medications was included, it is not possible to draw definitive conclusions about the effect of RIs on CYP2D6 IM. AUC for this subject 最後 The significantly higher values ​​compared to either healthy CYP2D6 IM subjects (6.90x), healthy CYP2D6 EM (32.1x), or CYP2D6 EM with severe RI (35.2x) contribute, at least in part, to the combined effect of the two concurrently administered CYP inhibitors, a CYP2D6 inhibitor (esitalopram) and a CYP3A inhibitor (amlodipine).

[0107] Safety results: A total of one mild TEAE was observed in one subject and was considered by investigators to be related to the study drug: fatigue in a healthy subject. No serious adverse events were reported, and there were no deaths or discontinuations due to AEs. There were no clinically relevant, procedure-induced PCSAs in terms of laboratory values, vital signs, or ECG.

[0108] Overall conclusion: The effect on mild and moderate hepatic impairment in the subjects was evaluated in the single-dose Phase 1 study described in Example 1. After a single 84 mg dose, eliglustat C 最大 And AUC was compared to healthy CYP2D6 EM in CYP2D6 with mild hepatic impairment. In EM, the risk of CYP2D6 was 1.22 times and 1.15 times higher, indicating moderate hepatic impairment. In EM, the figures were 2.81 times and 5.16 times higher.

[0109] Using a PBPK model, steady-state exposure was predicted in CYP2D6 EMs with mild and moderate hepatic impairment. For CYP2D6 EMs with hepatic impairment, we proposed doses of eliglustat that would provide an effective and safe mean steady-state exposure when administered alone or in combination with a CYP inhibitor. Therefore, in CYP2D6 rapid metabolites with mild hepatic impairment, dose adjustment (i.e., 84 mg BID) is not recommended when eliglustat is administered alone, and when eliglustat is taken with a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor, the eliglustat dose should be reduced to 84 mg QD. Because the mean steady-state exposure was predicted to be much higher than the upper limit of the effective and safe exposure range, eliglustat is contraindicated in CYP2D6 rapid metabolites with moderate hepatic impairment and CYP2D6 rapid metabolites with mild hepatic impairment when administered concomitantly with a strong or moderate CYP2D6 inhibitor. Due to the possibility of significantly elevated eliglustat plasma concentrations, eliglustat is contraindicated in patients with severe hepatic impairment. Because steady-state exposure is unknown, contraindications for eliglustat use have been proposed in CYP2D6 IM or PM patients with mild to moderate hepatic impairment.

[0110] The effect on severe renal impairment was increased in the single-dose Phase 1 study described in Example 2. After a single 84 mg dose, eliglustat C 最大 The AUC was similar in CYP2D6 EMs with severe renal impairment and in healthy CYP2D6 EMs.

[0111] Considering the lack of severe renal impairment after a single dose, it is expected that the time-dependent effect due to mechanism-based CYP2D6 inhibition is not affected by renal impairment. Therefore, repeated administration of eliglustat in CYP2D6 EM is not expected to affect eliglustat exposure. Accordingly, dose adjustments are not proposed for CYP2D6 EM with mild, moderate, and severe radioisotopes.

[0112] Data is limited or unavailable in CYP2D6 EM, IM, or PM with end-stage renal disease and in CYP2D6 IM or PM with mild, moderate, or severe renal impairment; the use of eliglustat should be avoided or is not recommended in these patients.

Claims

1. A pharmaceutical preparation for treating Gaucher disease in a patient with mild hepatic impairment and rapid metabolism of CYP2D6, comprising eliglustat or a pharmaceutically acceptable salt thereof, wherein the patient concurrently takes a drug that is a potent or moderate CYP3A inhibitor, and the pharmaceutical preparation comprises a once-daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form.

2. The pharmaceutical product according to claim 1, wherein the eliglustat or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

3. A pharmaceutical product for treating Gaucher disease in patients with severe renal impairment of the CYP2D6 rapid metabolic type, comprising eliglustat or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical product comprises a dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, measured in nucleotide form, twice daily.

4. The pharmaceutical product according to claim 3, wherein the eliglustat or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

5. A pharmaceutical formulation for treating Gaucher disease in a patient with mild hepatic impairment and rapid metabolism of CYP2D6, comprising eliglustat or a pharmaceutically acceptable salt thereof, to be taken by the patient in combination with a drug that is a potent or moderate CYP3A inhibitor, wherein the pharmaceutical formulation comprises a once-daily dose of 84 mg of eliglustat or a pharmaceutically acceptable salt thereof, as measured in nucleotide form.

6. The pharmaceutical product according to claim 5, wherein the eliglustat or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

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