Migalastat

Fabry disease is a progressive X-linked lysosomal storage disorder which affects males and females. Fabry disease-causing mutations in the GLA gene result in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) that is required for glycosphingolipid substrate (e.g., GL-3, lyso-Gb3) metabolism. Reduced α-Gal A activity is, therefore, associated with the progressive accumulation of substrate in vulnerable organs and tissues, which leads to the morbidity and mortality associated with Fabry disease.

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of α-Gal A. Migalastat is a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of α-Gal A, the genotypes of which are referred to as amenable mutations. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes. Once in lysosomes dissociation of migalastat restores α-Gal A activity, leading to the catabolism of GL-3 and related substrates.

Absorption

The absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75%. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC_0-∞) and C_max demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg.

Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC_0-∞) and reductions of 15% to 40% in mean peak migalastat exposure (C_max) compared with the fasting state.

Distribution

In healthy volunteers, the volume of distribution (V_z/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) ranged from 77 to 133 L, indicating it is well distributed into tissues and greater than total body water (42 litres). There was no detectable plasma protein binding following administration of [¹⁴C]-migalastat hydrochloride in the concentration range between 1 and 100 μM.

Biotransformation

Based upon in vivo data, migalastat is a substrate for UGT, being a minor elimination pathway. Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro and it is considered unlikely that migalastat would be subject to drug-drug interactions with cytochrome P450s. A pharmacokinetic trial in healthy male volunteers with 150 mg [¹⁴C]-migalastat HCl revealed that 99% of the radiolabeled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1 to M3 (13%). Approximately 9% of the total radioactivity was unassigned.

Elimination

A pharmacokinetic trial in healthy male volunteers with 150 mg [¹⁴C]-migalastat hydrochloride revealed that approximately 77% of the radiolabeled dose was recovered in urine of which 55% of was excreted as unchanged migalastat and 4% as combined metabolites M1, M2 and M3. Approximately 5% of the total sample radioactivity was unassigned components. Approximately 20% of the total radiolabeled dose was excreted in faeces, with unchanged migalastat being the only measured component.

Following ascending single oral doses (25-675 mg migalastat hydrochloride), no trends were found for clearance, CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr. Following administration of the same doses, the mean elimination half-life (t_1/2) ranged from approximately 3 to 5 hours.

Special populations

Patients with renal impairment

Migalastat has not been studied in patients with Fabry disease who have a GFR less than 30 mL/min/1.73 m². In a single dose study with migalastat in non-Fabry subjects with varying degrees of renal insufficiency, exposures were increased by 4.3-fold in subjects with severe renal impairment (GFR <30 mL/min/1.73 m²).

Patients with hepatic impairment

No studies have been carried out in subjects with impaired hepatic function. From the metabolism and excretion pathways, it is not expected that a decreased hepatic function may affect the pharmacokinetics of migalastat.

Elderly (>65 years)

Clinical studies of migalastat included small number of patients aged 65 and over. The effect of age was evaluated in a population pharmacokinetic analysis on plasma migalastat clearance in the ERT-naïve study population. The difference in clearance between Fabry patients ≥65 years and those <65 years was 20%, which was not considered clinically significant.

Gender

The pharmacokinetic characteristics of migalastat were not significantly different between females and males in either healthy volunteers or in patients with Fabry disease.

Non-clinical studies suggest no specific hazard for humans on the basis of single-and repeat-dose studies, with the exception of transient and fully reversible infertility in male rats associated with migalastat treatment. The infertility associated with migalastat treatment was reported at clinically relevant exposures. Complete reversibility was seen after 4 weeks off-dose. Similar findings have been noted pre-clinically following treatment with other iminosugars. In the rabbit embryo-foetal toxicity study, findings including embryo-foetal death, a reduction in mean foetal weight, retarded ossification, and slightly increased incidences of minor skeletal abnormalities were observed only at doses associated with maternal toxicity.

In a rat 104-week carcinogenicity study, there was an increased incidence of pancreatic islet cell adenomas in males at a dose level 19-fold higher than the exposure (AUC) at the clinically efficacious dose. This is a common spontaneous tumour in ad libitum-fed male rats. In the absence of similar findings in females, no findings in the genotoxicity battery or in the carcinogenicity study with Tg.rasH2 mice, and no pre-neoplastic pancreatic findings in the rodents or monkeys, this observation in male rats is not considered related to treatment and its relevance to humans is unknown.