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Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes

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Abstract

Purpose

This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects.

Methods

Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed-effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner.

Results

Indirect-response Imax models including circadian variation best described the effect of ponesimod on lymphocyte subsets. B cells and T helper cells were shown to be more affected compared to T cytotoxic cells with respect to the maximum possible reduction (100% for B and T helper cells, 95% for T cytotoxic cells) and the concentration required to reach half the maximum effect. Inter-individual variability was found to be larger for T cytotoxic compared to T helper, and B cells.

Conclusion

These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases.

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Abbreviations

amp:

Amplitude of the circadian rhythm

GOF:

Goodness-of-fit

IC50 :

Drug concentration required to achieve the half-maximum inhibitory effect

IIV:

Inter-individual variability

Imax :

Maximum possible drug effect (lymphocyte reduction)

IWRES:

Individual-weighted residuals

kout :

First-order rate constant describing disappearance of lymphocytes from the blood stream

pcVPC:

Prediction-corrected visual predictive check

PD:

Pharmacodynamic(s)

PK:

Pharmacokinetic(s)

Rin :

Zero-order rate describing appearance of lymphocytes in the blood stream

S1P(1) :

Sphingosine-1-phosphate (1)

SAEM:

Stochastic approximation of expectation maximization

shift:

Circadian time shift

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Author information

Authors and Affiliations

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

    Dominik Lott & Thorsten Lehr

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

    Dominik Lott, Andreas Krause & Jasper Dingemanse

  3. Department of Global Clinical Science and Epidemiology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

    Christian A. Seemayer

  4. Department of Translational Science Biology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

    Daniel S. Strasser

Authors
  1. Dominik Lott
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  2. Andreas Krause
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  4. Daniel S. Strasser
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  5. Jasper Dingemanse
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Corresponding author

Correspondence to Dominik Lott.

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Lott, D., Krause, A., Seemayer, C.A. et al. Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes. Pharm Res 34, 599–609 (2017). https://doi.org/10.1007/s11095-016-2087-x

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  • DOI: https://doi.org/10.1007/s11095-016-2087-x

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