Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: favorable impact of dose up-titration

• Published in: Journal of clinical pharmacology Vol. 54; no. 2; p. 179
• Main Authors: Brossard, P, Scherz, M, Halabi, A, Maatouk, H, Krause, A, Dingemanse, J
• Format: Journal Article
• Language: English
• Published: England 01.02.2014
• Subjects: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Lymphocyte Count; Male; Middle Aged; Models, Biological; Receptors, Lysosphingolipid - antagonists & inhibitors; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Young Adult; S1P1 receptor modulator; pharmacokinetics; ponesimod; healthy subjects; pharmacodynamics
• DOI: 10.1002/jcph.244

This multiple-ascending-dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod-induced heart rate (HR) reduction and PR-prolongation. This elicited the design of an up-titration schedule in 17 subjects to a dose of 40 mg in part B. The up-titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple-dose pharmacokinetics were slightly more than dose-proportional and characterized by a time to maximum concentration and an elimination half-life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3-fold. Ponesimod caused a dose-dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic-pharmacodynamic model enabled comparing day 1 and steady-state conditions. These results warrant further investigation of ponesimod in patients.