Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first‐in‐human study. (December 2013)

• Record Type: Journal Article
• Authors: Brossard, Patrick; Derendorf, Hartmut; Xu, Jian; Maatouk, Haidar; Halabi, Atef; Dingemanse, Jasper
• Is Part Of: British journal of clinical pharmacology. Volume 76:Number 6(2013:Dec.)
• Page Start: 888
• Page End: 896
• Publication Date: 2013-12
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12129
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12129-sec-0001" sec-type="section"> <title>Aims</title> <p>This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine‐1‐phosphate (S1P<sub>1</sub>) receptor modulator in development for the treatment of auto‐immune diseases.</p> </sec> <sec id="bcp12129-sec-0002" sec-type="section"> <title>Methods</title> <p>This was a double‐blind, placebo‐controlled, ascending, single‐dose study. Healthy male subjects received doses of 1–75 mg or placebo control.</p> </sec> <sec id="bcp12129-sec-0003" sec-type="section"> <title>Results</title> <p>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.</p> </sec> <sec id="bcp12129-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>