Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first‐in‐human study

• Published in: British journal of clinical pharmacology Vol. 76; no. 6; pp. 888 - 896
• Main Authors: Brossard, Patrick, Derendorf, Hartmut, Xu, Jian, Maatouk, Haidar, Halabi, Atef, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.12.2013
• Subjects: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Immunologic Factors - adverse effects; Immunologic Factors - pharmacokinetics; Immunologic Factors - pharmacology; Lymphocyte Count; Lymphocytes - cytology; Lymphocytes - drug effects; Male; Middle Aged; Models, Biological; pharmacodynamics; Pharmacokinetics; ponesimod; Receptors, Lysosphingolipid - metabolism; S1P1 receptor modulator; safety and tolerability; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; total lymphocyte count; Young Adult; S1P1 receptor modulator; pharmacokinetics; ponesimod; total lymphocyte count; safety and tolerability; pharmacodynamics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12129

Aims This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine‐1‐phosphate (S1P1) receptor modulator in development for the treatment of auto‐immune diseases. Methods This was a double‐blind, placebo‐controlled, ascending, single‐dose study. Healthy male subjects received doses of 1–75 mg or placebo control. Results Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half‐life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose‐dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts. Conclusions Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single‐dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once‐a‐day dosing.