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Eur J Pharm Sci. 2014 Oct 15;63:147-53. doi: 10.1016/j.ejps.2014.07.005. Epub 2014 Jul 19.

Clinical pharmacology of ponesimod, a selective S1P₁ receptor modulator, after uptitration to supratherapeutic doses in healthy subjects.

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Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. Electronic address:
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
Quintiles Drug Research Unit at Guy's Hospital, London, United Kingdom.



The aim of this study was to assess in healthy subjects the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an oral selective sphingosine-1-phosphate receptor 1 (S1P1) modulator in development for multiple sclerosis, by using an uptitration scheme up to supratherapeutic doses.


This was a double-blind, placebo-controlled, randomised, parallel group, uptitration study. Male and female subjects received ascending oral doses of ponesimod (n=12) or placebo (n=4) once daily for 3 days at each dose level (10-20-40-60-80-100mg).


The most frequent adverse events were chest discomfort, headache, dizziness, dyspnoea, abdominal pain, and night sweats. Chest discomfort and dyspnoea were considered dose-limiting. A transient decrease in heart rate was observed following the first 10-mg ponesimod dose (maximum mean decrease of 9 beats per minute (bpm) (placebo: 2 bpm)). After uptitration, effects on heart rate were indistinguishable from placebo. A dose-dependent effect on pulmonary function tests was observed and reached a plateau with 60-80 mg ponesimod (maximum mean decrease from baseline of 1.24l (-30.5%) in forced expiratory volume in 1s). A plateau in mean lymphocyte count reduction of approximately 70% from baseline was reached at the 40 mg dose level. Observed effects were fully reversible within 10days after treatment discontinuation. No relevant sex differences were observed.


At supratherapeutic doses, symptoms of chest discomfort and dyspnoea were dose-limiting. An uptitration dosing scheme is to be preferred in clinical studies in patients in order to limit effects of ponesimod on heart rate and atrioventricular (AV) conduction.


Heart rate reduction; Pharmacodynamics; Pharmacokinetics; Ponesimod; S1P(1) receptor modulator; Safety and tolerability

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