Background and objectives: The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2-4 h] and a terminal half-life (t ½) of 32 h 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.
Methods: After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase.
Results: The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2-87.5]. CL and V ss (95 % CI) were 3.8 L/h (3.3-4.3) and 160 L (146.1-174.2), respectively. C max (95 % CI) was 48.5 ng/mL (43.9-53.6) and 61.4 ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. The t ½ (95 % CI) following intravenous infusion was 32.9 h (28.5-38.1) and 31.7 h (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.
Conclusions: This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.