Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects

• Published in: Drugs in R&D Vol. 15; no. 2; pp. 203 - 210
• Main Authors: Juif, Pierre-Eric, Hoch, Matthias, D’Ambrosio, Daniele, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2015; Springer Nature B.V
• Subjects: Adult; Area Under Curve; Biological Availability; Capsules - administration & dosage; Capsules - pharmacokinetics; Chemistry, Pharmaceutical - methods; Clinical trials; Cross-Over Studies; Drug dosages; Electrocardiography; Female; Healthy Volunteers; Heart rate; Humans; Internal Medicine; Lymphocytes; Male; Medical laboratories; Medicine; Medicine & Public Health; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Receptors, Lysosphingolipid - metabolism; Tablets - administration & dosage; Tablets - pharmacokinetics; Therapeutic Equivalency; Thiazoles - administration & dosage; Thiazoles - pharmacokinetics; Vital signs; United States > US; Multiple Sclerosis; Lymphocyte Count; Polymorphic Form; Tablet Formulation; Capsule Formulation
• ISSN: 1174-5886; 1179-6901; 1179-6901
• DOI: 10.1007/s40268-015-0095-7

Background Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P 1 ) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P 1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis). Objectives 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 (AUC 0–inf ), the area under the curve from time zero to the time of the last measurable concentration (AUC 0–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. Conclusion The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.