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

Br J Clin Pharmacol. 2013 Dec;76(6):888-96. 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.

Keywords: S1P1 receptor modulator; pharmacodynamics; pharmacokinetics; ponesimod; safety and tolerability; total lymphocyte count.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Receptors, Lysosphingolipid / metabolism*
  • Thiazoles* / adverse effects
  • Thiazoles* / pharmacokinetics
  • Thiazoles* / pharmacology
  • Young Adult


  • Immunologic Factors
  • Receptors, Lysosphingolipid
  • Thiazoles
  • ponesimod