Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects.
BACKGROUND
Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).


OBJECTIVE
The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).


METHODS
Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.


RESULTS
Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0-inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0-t), the terminal half-life (t ½), and the maximum plasma concentration (C max) were all within the 0.80-1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.


CONCLUSIONS
The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
Pierre-Eric
PE
Juif
Matthias
M
Hoch
Daniele
D
D'Ambrosio
Jasper
J
Dingemanse
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018592:Cross-Over Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013607:Tablets / Q000008:administration & dosage / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D002214:Capsules; D049349:Receptors, Lysosphingolipid; D013607:Tablets; D013844:Thiazoles; C550169:ponesimod