title: Effect of ponesimod, a selective S1P1 receptor modulator, on the QT interval in healthy individuals.
abstract: Ponesimod is an orally active selective sphingosine-1-phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single-centre, double-blind, randomized, placebo- and positive-controlled parallel-group study investigating the effects of ponesimod on the QTc interval in healthy individuals. A nested cross-over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10-100 mg ponesimod according to an uptitration regimen on days 2-23 and moxifloxacin-matching placebo on days 1 and 24. Subjects in group B received ponesimod-matching placebo on days 2-23 and were randomized to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary end-point was the baseline-adjusted, placebo-corrected effect on the individually corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two-sided confidence interval (CI): 2.5-11.3) and 9.1 ms (90% CI: 4.1-14.0) for doses of 40 mg and 100 mg, respectively. A concentration-effect analysis confirmed the QTcI-prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration-effect analysis, the QTc prolongation caused by 20 mg ponesimod and the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e. an upper bound of the two-sided 90% CI of ≥10 ms).
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Patrick
authors.initials: P
authors.lastname: Brossard
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.forename: Randall
authors.initials: R
authors.lastname: Stoltz
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D018570:Risk Assessment; D000081025:Sphingosine-1-Phosphate Receptors; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D024841:Fluoroquinolones; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D013844:Thiazoles; C550169:ponesimod; D000077266:Moxifloxacin