Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study

Abstract

Aims: This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P1) receptor modulator in development for the treatment of auto-immune diseases.

Methods: This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1-75 mg or placebo control.

Results: Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts.

Conclusions: Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.

Keywords: S1P1 receptor modulator; pharmacodynamics; pharmacokinetics; ponesimod; safety and tolerability; total lymphocyte count.

Figure 1

Arithmetic mean maximal change from baseline (and SD) for heart rate as recorded by 12-lead electrocardiogram in the supine position after single-dose administration of placebo (n = 12) or ponesimod at doses of 1, 3, 8, 20, 50 or 75 mg (n = 6 per dose group)

Figure 2

Arithmetic mean (and SD) plasma concentration–time profiles of ponesimod in healthy subjects (n = 6 per dose group) after administration of single doses of 1, 3, 8, 20, 50 or 75 mg of ponesimod (linear scale). The inset shows the profiles on a semilogarithmic scale. For clarity, SD is displayed only for ponesimod doses ≥20 mg for the profiles on the linear scale. , 1 mg; , 3 mg; , 8 mg; , 20 mg; , 50 mg; , 75 mg

Figure 3

Effect–time profiles of the mean (and SD) change from baseline (%) for total lymphocyte count after single-dose administration of placebo (n = 12) or ponesimod at doses of 1, 3, 8, 20, 50 or 75 mg (n = 6 per dose group). , 1 mg; , 3 mg; , 8 mg; , 20 mg; , 50 mg; , 75 mg; , placebo

Figure 4

Pharmacokinetic/pharmacodynamic model including the circadian rhythm of cortisol: observed time course (symbols) and predicted time course (lines) of the percentage change from baseline in total lymphocyte count after administration of 8, 20, 50 or 75 mg of ponesimod. The observed values represent the mean (and SD) of data from n = 12 subjects on placebo and n = 6 subjects on the ponesimod doses. The continuous lines are model-predicted population profiles based on mean total lymphocyte percentage data. , placebo; , 8 mg; , 20 mg; , 50 mg; , 75 mg