Absolute Bioavailability of Ponesimod, a Selective S1P1 Receptor Modulator, in Healthy Male Subjects.

Abstract

The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, ischaracterized by a rapid absorption [time to maximum concentration (t max) of 2-4h] and a terminal half-life (t ½) of 32h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)]in healthy male subjects. After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10mg oral) main phase. The absolute bioavailability of ponesimod was 83.8% [90% confidence interval (CI): 80.2-87.5]. CL and V ss(95% CI) were 3.8L/h (3.3-4.3) and 160L (146.1-174.2), respectively. C max(95% CI) was 48.5ng/mL (43.9-53.6) and 61.4ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. Thet ½(95% CI)following intravenous infusion was 32.9h (28.5-38.1) and 31.7h (27.9-36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate. This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.