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

Abstract

PURPOSE:

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.

METHODS:

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).

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: M Hoch, D D'Ambrosio, D Wilbraham, P Brossard, J Dingemanse
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 63 Pg. 147-53 (Oct 15 2014) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 25046167 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2014. Published by Elsevier B.V.

Chemical References

• Receptors, Lysosphingolipid
• Thiazoles
• ponesimod

Topics

• Adolescent
• Adult
• Aged
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Receptors, Lysosphingolipid (metabolism)
• Thiazoles (administration & dosage, adverse effects, pharmacology)
• Young Adult