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Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis

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Abstract

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing–remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33 h (accumulation factor of 2- to 2.6-fold), and fast and almost complete oral absorption (absolute oral bioavailability: 84%), reaching peak plasma and blood concentrations within 2–4 h. Ponesimod is highly metabolized, and the parent compound along with its two major (non-clinically active) metabolites are mainly excreted in the feces (recovery: 57.3–79.6%) and to a lesser extent in the urine (recovery: 10.3–18.4%). Additionally, the population PKPD model characterized the ponesimod effects on heart rate: a transient, dose-dependent decrease in heart rate in the first days of dosing, that is mitigated by administering the first doses of ponesimod treatment using a gradual up-titration schedule, before reaching the daily maintenance dose of 20 mg. This selected maintenance dose has been shown to be superior in reducing annualized relapse rate (ARR) when compared with teriflunomide in a pivotal phase III study. Furthermore, a dose-dependent reduction of peripheral lymphocyte counts that is sustained with continued daily oral dosing of ponesimod and is rapidly (4–7 days) reversible upon drug discontinuation has been characterized with an indirect response model.

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Acknowledgements

The authors would like to express their sincere gratitude to the study participants. This study could not have been accomplished without their contributions. The authors thank Italo Poggesi, Per Olsson Gisleskog, Quentin Leirens, and Nicolas Luyckx for their contributions to the study and all the investigators and their staff for their participation. Writing and editorial support was provided by Colleen Elliott, PhD of CME Science Writers, LLC.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, 1125 Trenton Harborton Road, Titusville, NJ, 08560, USA

    Terra M. Kruger

  2. Department of Research and Drug Development, Janssen-Cilag Spain, Part of Janssen Pharmaceutical Companies, Madrid, Spain

    Belén Valenzuela & Juan Jose Perez Ruixo

  3. Janssen Research & Development, Preclinical Sciences and Translational Safety, Spring House, PA, USA

    Charles D. Thompson

  4. Department of Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, Beerse, Belgium

    Sivi Ouwerkerk-Mahadevan

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  1. Terra M. Kruger
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Corresponding author

Correspondence to Terra M. Kruger.

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Conflict of interest statement

All authors hold stock in Johnson & Johnson.

Funding source

This study is supported by Actelion Pharmaceuticals, Part of Janssen Pharmaceutical Companies, Allschwil, Switzerland.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Protocols were reviewed and approved by an institutional review board.

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Freely given, informed consent to participate was obtained for all human participants in this study.

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Data sharing/availability is not applicable to this manuscript as no new data were created or analyzed for this review article.

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All authors participated in the original design of the manuscript, monitored literature data and contributed to the data interpretation, development and review of this manuscript and confirm that they have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the literature data, provided direction and comments on the manuscript, made the final decision about where to publish these data and approved submission to this journal.

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Kruger, T.M., Valenzuela, B., Thompson, C.D. et al. Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis. Clin Pharmacokinet 62, 1533–1550 (2023). https://doi.org/10.1007/s40262-023-01308-5

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  • DOI: https://doi.org/10.1007/s40262-023-01308-5

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