Dataset Information

Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

ABSTRACT: Istradefylline, a selective adenosine A2A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: Cmax , 0.55 (90%CI, 0.49-0.62); AUClast , 0.21 (90%CI, 0.19-0.22); and AUCinf , 0.19 (90%CI, 0.18-0.20), indicating nonequivalence. These changes were primarily because of the effect of rifampin on the elimination parameters of istradefylline; mean CL/F was increased from 4.0 to 20.6 L/h, and mean t1/2 was reduced from 94.8 to 31.5 hours. The effect of rifampin coadministration on the disposition of the istradefylline M1 and M8 metabolites was inconsistent and variable. Furthermore, as exposure of the istradefylline M1 and M8 metabolites in plasma was generally <9% of total drug exposure, it would be expected to have a negligible impact on the pharmacodynamic effect of istradefylline. Caution should be exercised when istradefylline is administered concurrently with strong CYP3A4 inducers and dose adjustment considered.

SUBMITTER: Mukai M

PROVIDER: S-EPMC5811788 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

Mukai Mayumi M Uchimura Tatsuo T Zhang Xiaoping X Greene Douglas D Vergeire Maria M Cantillon Marc M

Journal of clinical pharmacology 20170907 2

Istradefylline, a selective adenosine A<sub>2A</sub> inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric ...[more]

PMID: 28881378

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Project description:ObjectiveFabry 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.MethodsIn 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 numberClinicalTrials.gov registration identifier is NCT01853852.ResultsMedian 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.ConclusionsThis 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.

Dataset Information

Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

Publications

Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

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