title: Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: favorable impact of dose up-titration.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Brossard
authors.forename: M
authors.initials: M
authors.lastname: Scherz
authors.forename: A
authors.initials: A
authors.lastname: Halabi
authors.forename: H
authors.initials: H
authors.lastname: Maatouk
authors.forename: A
authors.initials: A
authors.lastname: Krause
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: S1P1 receptor modulator; healthy subjects; pharmacodynamics; pharmacokinetics; ponesimod