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Multiple‐dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P 1 receptor modulator: Favorable impact of dose up‐titration
Author(s) -
Brossard P.,
Scherz M.,
Halabi A.,
Maatouk H.,
Krause A.,
Dingemanse J.
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.244
Subject(s) - pharmacokinetics , pharmacodynamics , medicine , tolerability , pharmacology , anesthesia , adverse effect
This multiple‐ascending‐dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P 1 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.