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Absolute Bioavailability of Ponesimod, a Selective S1P1 Receptor Modulator, in Healthy Male Subjects

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Abstract

Background and Objectives

The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2–4 h] and a terminal half-life (t ½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)] in healthy male subjects.

Methods

After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase.

Results

The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2–87.5]. CL and V ss (95 % CI) were 3.8 L/h (3.3–4.3) and 160 L (146.1–174.2), respectively. C max (95 % CI) was 48.5 ng/mL (43.9–53.6) and 61.4 ng/mL (55.3–68.3) after intravenous infusion and oral administration, respectively. The t ½ (95 % CI) following intravenous infusion was 32.9 h (28.5–38.1) and 31.7 h (27.9–36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate.

Conclusions

This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.

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Fig. 1

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Acknowledgments

The authors wish to express their thanks to Isabelle Naëije and Anne-Hélène Clugery for project management, Adil Aouboukdir for monitoring, Susanne Globig for bioanalytical conduct, Andrea Vaclavkova for drug safety, Daniela Baldoni for pharmacokinetic evaluation, and Dr Salvatore Febbraro (Principal investigator, Simbec Research Ltd).

Authors’ contribution

Performed study design: MH and JD.

Performed data analysis: PEJ and MH.

Wrote or contributed to the writing of the manuscript: MB, PEJ, MH, and JD.

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Authors and Affiliations

Authors

Corresponding author

Correspondence to Pierre-Eric Juif.

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Funding

This study was sponsored by Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

Conflict of interest

MB, PEJ, and JD are current employees of Actelion Pharmaceuticals Ltd. MH is a former employee of Actelion Pharmaceuticals Ltd.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments), and the South East Wales Research Ethics Committee B (UK) approved the study.

Informed consent

Written informed consent was obtained from all subjects participating in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

13318_2016_325_MOESM1_ESM.tif

Supplementary material 1. Figure S1: Mean (± SD) lymphocyte count vs. time profile from 0 to 144 h (panel A) and from 0 to 16 h (panel B) and mean (± SD) heart rate vs. time profile from 0 h to 144 h (panel C) and from 0 to 10 h (panel D), after intravenous infusion of a 5 mg dose (main phase, n = 14), or oral administration of a 10 mg dose (main phase, n = 14) ponesimod. The thick bar on the top represents the duration of infusion of intravenous dose (i.e., 3 h). The two horizontal bars represent the lymphocyte count or heart rate at baseline (solid line: intravenous; dotted line: oral) (TIFF 451 kb)

13318_2016_325_MOESM2_ESM.docx

Supplementary material 2. Table S1: Demographic variables of subjects enrolled in the pilot phase and the main phase (DOCX 14 kb)

13318_2016_325_MOESM3_ESM.docx

Supplementary material 3. Table S2: Treatment-emergent adverse events, in the pilot phase and the main phase (DOCX 14 kb)

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Boehler, M., Juif, PE., Hoch, M. et al. Absolute Bioavailability of Ponesimod, a Selective S1P1 Receptor Modulator, in Healthy Male Subjects. Eur J Drug Metab Pharmacokinet 42, 129–134 (2017). https://doi.org/10.1007/s13318-016-0325-6

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  • DOI: https://doi.org/10.1007/s13318-016-0325-6

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