title: Clinical pharmacology of ponesimod, a selective S1P₁ receptor modulator, after uptitration to supratherapeutic doses in healthy subjects.
abstract: OBJECTIVE
  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.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. Electronic address: matthias.hoch@actelion.com.
authors.forename: M
authors.initials: M
authors.lastname: Hoch
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: D'Ambrosio
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, London, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Wilbraham
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Brossard
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: Heart rate reduction; Pharmacodynamics; Pharmacokinetics; Ponesimod; S1P(1) receptor modulator; Safety and tolerability