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Impact of Demographics, Organ Impairment, Disease, Formulation, and Food on the Pharmacokinetics of the Selective S1P1 Receptor Modulator Ponesimod Based on 13 Clinical Studies

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Abstract

Background

Ponesimod is a selective, orally active sphingosine-1-phosphate receptor 1 modulator currently undergoing clinical evaluation for the treatment of multiple sclerosis (MS) in phase III clinical trials. Ponesimod dose-dependently reduces peripheral blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs.

Methods

A population pharmacokinetic (PK) analysis was performed based on pooled data from 13 clinical studies. Interindividual variability (IIV) and the impact of key demographic variables and other covariates on ponesimod exposure were assessed quantitatively.

Results

A two-compartment model with sequential zero/first-order absorption, including lag time, intercompartmental drug flow, and first-order clearance, adequately described the PK of ponesimod. Body weight, race, MS, psoriasis, hepatic impairment, drug formulation, and food were identified to significantly affect the concentration–time profile. The inclusion of these covariates into the model explained approximately 25 % of the IIV in the PK of ponesimod. Model predictions indicated that the impact of the identified covariates on ponesimod steady-state exposure is within 20 % of exposure, and thus within the margins of the IIV, with the exception of hepatic impairment. Changes up to threefold were predicted for severe cases of liver dysfunction.

Conclusion

The rich data set enabled building a comprehensive population PK model that accurately predicts the concentration–time data of ponesimod. Covariates other than hepatic impairment were considered not clinically relevant and thus do not require dose adjustment. A potential dose adaptation can be conducted based on the final model.

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Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, Saarland University, 66123, Saarbrücken, Germany

    Dominik Lott & Thorsten Lehr

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

    Dominik Lott, Jasper Dingemanse & Andreas Krause

Authors
  1. Dominik Lott
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  2. Thorsten Lehr
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  3. Jasper Dingemanse
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  4. Andreas Krause
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Corresponding author

Correspondence to Dominik Lott.

Ethics declarations

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. Informed consent was obtained from all individual participants included in this study.

Funding

The studies were funded by Actelion Pharmaceuticals Ltd.

Conflict of interest

Dominik Lott, Jasper Dingemanse, and Andreas Krause are employees of Actelion Pharmaceuticals Ltd. Thorsten Lehr has reported no potential conflicts of interest.

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Lott, D., Lehr, T., Dingemanse, J. et al. Impact of Demographics, Organ Impairment, Disease, Formulation, and Food on the Pharmacokinetics of the Selective S1P1 Receptor Modulator Ponesimod Based on 13 Clinical Studies. Clin Pharmacokinet 56, 395–408 (2017). https://doi.org/10.1007/s40262-016-0446-8

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