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

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 (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.

Keywords::

• Migalastat HCl
• GR181413
• AT1001
• Pharmacologic chaperone
• Fabry disease
• Pharmacokinetics
• Japanese

Transparency

Declaration of funding

This study and its publication were funded by GlaxoSmithKline, Research Triangle Park, NC, and Amicus Therapeutics, Cranbury, NJ.

Declaration of financial/other relationships

PNM Jr is employed by GlaxoSmithKline, USA, and holds stock in the company. HI, NT, TT, and TH are employed by GlaxoSmithKline K.K., Japan. TH holds stock in the company. None of the other Japanese authors hold stocks in the company.

Acknowledgments

The authors would like to thank Jennifer Yuan, MD, PhD, and Paul S. Thomas, MD, PhD (study investigators), and study volunteers for their participation, as well as Franziska Loehrer, PhD, MRQA, Cheryl Friend, and the staff at GlaxoSmithKline Medicines Research Unit in Sydney, Australia, for support in conducting the study. Professional medical writing and editorial assistance was provided by Stephanie Finucane, MS, CMPP of Caudex Medical, New York, and was funded by Amicus Therapeutics and GlaxoSmithKline.