title: Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive.
abstract: OBJECTIVE
  To determine the effects of steady-state concentrations of the selective S1P1 receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive.
  
  
  METHODS
  Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis.
  
  
  RESULTS
  Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of Cmax and AUC0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of Cmax and AUC0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline.
  
  
  CONCLUSIONS
  No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Maribel
authors.initials: M
authors.lastname: Reyes
authors.forename: Patrick
authors.initials: P
authors.lastname: Brossard
authors.forename: Didier
authors.initials: D
authors.lastname: Chassard
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; D004997:Ethinyl Estradiol; C550169:ponesimod; D009640:Norethindrone