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

• Published in: Journal of drug assessment (London, U.K.) Vol. 2; no. 1; pp. 87 - 93
• Main Authors: Ino, Hiroko, Takahashi, Naoki, Terao, Takumi, Mudd, Paul N., Hirama, Toshiyasu
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.01.2013; Taylor & Francis; Maney Publishing
• Subjects: AT1001; Fabry disease; GR181413; Japanese; Migalastat HCl; Original; Pharmacokinetics; Pharmacologic chaperone; Migalastat HCl; AT1001; Pharmacologic chaperone; Fabry disease; GR181413; Pharmacokinetics; Japanese
• ISSN: 2155-6660; 2155-6660
• DOI: 10.3109/21556660.2013.827117

Abstract 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 (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC), apparent terminal-phase half-life (t1/2), 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 tmax of migalastat was 3.0-3.5 h. Migalastat HCl concentrations declined relatively rapidly, with a mean t1/2 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 Cmax 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.