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Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Conclusion

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.

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Abbreviations

NET:

Norethisterone

EE:

Ethinyl estradiol

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Acknowledgments

The authors would like to thank Dr Dikran Mouradian, principal investigator of this study, Marzia Cavallaro for the statistical analysis, Kasra Shakeri-Nejad and Wenting Zhang-Fu for their medical input and assessment, Swiss Bioanalytics, Birsfelden, Switzerland for analysis of ponesimod, and PPD Richmond, VA, USA for analysis of NET and EE.

Conflict of interest/Disclosure

Actelion Pharmaceuticals Ltd provided the funding for this clinical trial. Maribel Reyes, Matthias Hoch, and Jasper Dingemanse are full time employees of Actelion Pharmaceuticals Ltd. Patrick Brossard is a former employee of Actelion Pharmaceuticals Ltd. Didier Chassard is a full time employee of Biotrial.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Maribel Reyes, Patrick Brossard, Matthias Hoch & Jasper Dingemanse

  2. Biotrial Paris, 1 rue Charles Drot, 92500, Rueil-Malmaison, Paris, France

    Didier Chassard

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  1. Maribel Reyes
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  2. Patrick Brossard
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Corresponding author

Correspondence to Jasper Dingemanse.

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Author Contributions

Maribel Reyes was the lead author, and wrote, and directed the manuscript content of each draft. Patrick Brossard and Jasper Dingemanse designed and evaluated the research. Didier Chassard and Matthias Hoch carefully reviewed the manuscript drafts. All authors reviewed, interpreted the data, and agreed on the content. All authors approved the final version for submission.

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Reyes, M., Brossard, P., Chassard, D. et al. Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive. Eur J Clin Pharmacol 70, 287–293 (2014). https://doi.org/10.1007/s00228-013-1625-2

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  • DOI: https://doi.org/10.1007/s00228-013-1625-2

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