Pharmacokinetics, safety, and tolerability following single-dose migalastat hydrochloride (GR181413A/AT1001) in healthy male Japanese subjects

OBJECTIVE Fabry disease is a rare X-linked disease caused by mutations to the GLA gene, resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A. This study evaluated the pharmacokinetics, safety, and tolerability of ascending single doses of oral migalastat hydrochloride (HCl), an investigational drug, in healthy Japanese volunteers. METHODS In this phase I, randomized, placebo-controlled, single-blind, ascending single-dose, cross-over study, migalastat HCl (50 mg, 150 mg, or 450 mg) or placebo was administered orally to 14 fasting male Japanese volunteers (aged 20-55 years) on 4 non-consecutive days. Main plasma and urine pharmacokinetic end-points included maximum observed plasma concentration (C max), time to C max (t max), area under the plasma concentration-time curve (AUC), apparent terminal-phase half-life (t 1/2), urinary recovery of unchanged drug, renal clearance, and percentage of drug excreted in urine. Safety end-points included adverse events, clinical signs and symptoms (e.g., hematology, chemistry, and urinalysis), vital signs (blood pressure and heart rate), and 12-lead electrocardiogram. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov registration identifier is NCT01853852. RESULTS Median t max of migalastat was 3.0-3.5 h. Migalastat HCl concentrations declined relatively rapidly, with a mean t 1/2 of 3.2-4.0 h. The amount of migalastat HCl recovered in the urine and the percentage of migalastat HCl excreted unchanged over 24 h were consistent (∼45-50%) across the dose range. The AUC and C max of migalastat HCl were dose proportional from 50-450 mg. Safety results were similar to those observed in non-Japanese populations. CONCLUSIONS This study demonstrated that ascending single doses of migalastat HCl (50 mg, 150 mg, 450 mg) are absorbed at a moderate rate and eliminated relatively rapidly, with a safety profile consistent with that observed in non-Japanese populations. These results confirm the dose-proportional pharmacokinetics of migalastat HCl from 50-450 mg. This study was limited by a small subject population and a short-term follow-up.