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Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator

  • Andreas Krause
  • Patrick Brossard
  • Daniele D’Ambrosio
  • Jasper Dingemanse
Original Paper

Abstract

Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9 % and a maximum inhibition of 86 % of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 109 counts/L.

Keywords

Population pharmacokinetics/pharmacodynamics S1P1 receptor modulator Total lymphocyte count Indirect-effect model Circadian variation 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Andreas Krause
    • 1
  • Patrick Brossard
    • 1
  • Daniele D’Ambrosio
    • 2
  • Jasper Dingemanse
    • 1
  1. 1.Department of Clinical PharmacologyActelion Pharmaceuticals LtdAllschwilSwitzerland
  2. 2.Department of Clinical Science & EpidemiologyActelion Pharmaceuticals LtdAllschwilSwitzerland

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