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

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 42; no. 1; pp. 129 - 134
• Main Authors: Boehler, Margaux, Juif, Pierre-Eric, Hoch, Matthias, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2017
• Subjects: Biomedical and Life Sciences; Biomedicine; Human Physiology; Medical Biochemistry; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Short Communication; Absolute Bioavailability; Fingolimod; Intravenous Infusion; Main Phase; Progressive Multifocal Leukoencephalopathy
• ISSN: 0378-7966; 2107-0180; 2107-0180
• DOI: 10.1007/s13318-016-0325-6

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.