title: Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.
abstract: Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval.
authors.affiliation: Departments of Clinical Pharmacology and Business & Science Affairs, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Scherz
authors.forename: Patrick
authors.initials: P
authors.lastname: Brossard
authors.forename: Daniele
authors.initials: D
authors.lastname: D'Ambrosio
authors.forename: Murat
authors.initials: M
authors.lastname: Ipek
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019055:No-Observed-Adverse-Effect Level; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity*; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: S1P1 receptor modulator; desensitization; healthy subjects; ponesimod; up-titration regimen