title: Mitigation of Initial Cardiodynamic Effects of the S1P1Receptor Modulator Ponesimod Using a Novel Up-Titration Regimen.
abstract: Ponesimod, a potent selective sphingosine-1-phosphate receptor 1 modulator, leads to a reduction in circulating total lymphocyte count and transient decreases in heart rate (HR). Based on a modeling and simulation approach, this study was conducted to investigate whether a gradual up-titration regimen may mitigate these cardiodynamic effects. In this double-blind, placebo-controlled, randomized, 2-way crossover study, 32 healthy participants (15 males) received placebo on day 1 followed by multiple-dose administration of either ponesimod or placebo (ratio 3:1). Ponesimod was administered alternately using regimen A (incremental dose increase from 2 to 20 mg in 9 steps) or B (10 mg for 7 days followed by a single-dose administration of 20 mg). Cardiodynamic (Holter and 12-lead ECG), pharmacokinetic, pharmacodynamic (total lymphocyte count), and safety variables were assessed. After first-dose ponesimod administration (day 2), a transient decrease in HR was observed (nadir 2-3 hours postdose, back to predose values within 4-5 hours) of approximately 6 and 12 beats/min (bpm) (mean) following regimens A and B, respectively. On day 2, occurrence of HR <45 bpm, HR decrease from baseline of over 20 bpm, PR interval ≥200 milliseconds, or PR interval increase from baseline >20 ms, was lower following regimen A than B (14 vs 43 events). During the course of the study, incidence of HR <45 bpm was lower following regimen A than B (20 vs 58 events). Fewer participants reported adverse events following regimen A than B. Pharmacokinetics and pharmacodynamics were similar between the regimens. The novel gradual up-titration with ponesimod markedly mitigated initial cardiodynamic effects.
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Pierre-Eric
authors: PE
authors: Juif
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Matthias
authors: M
authors: Hoch
authors: Department of Global Drug Safety, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Andrea
authors: A
authors: Vaclavkova
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Andreas
authors: A
authors: Krause
authors: Covance Clinical Research Unit Ltd, Leeds, United Kingdom.
authors: Jim
authors: J
authors: Bush
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Jasper
authors: J
authors: Dingemanse
mesh_terms: 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; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: S1P1 receptor modulator; heart rate; ponesimod; tolerability; up-titration