Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects

• Published in: Clinical pharmacokinetics Vol. 58; no. 3; pp. 349 - 361
• Main Authors: Gardin, Anne, Ufer, Mike, Legangneux, Eric, Rossato, Gianluca, Jin, Yi, Su, Zhenzhong, Pal, Parasar, Li, Wenkui, Shakeri-Nejad, Kasra
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2019; Springer Nature B.V
• Subjects: Adolescent; Adult; Antifungal agents; Azetidines - administration & dosage; Azetidines - pharmacokinetics; Benzyl Compounds - administration & dosage; Benzyl Compounds - pharmacokinetics; Clinical medicine; Cytochrome; Cytochrome P-450 CYP2C9 - drug effects; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 CYP2C9 Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - therapeutic use; Drug dosages; Drug Interactions; Drug Therapy, Combination - methods; Enzymes; Female; Fluconazole - administration & dosage; Genotype; Genotype & phenotype; Healthy Volunteers - statistics & numerical data; Humans; Internal Medicine; Male; Medical research; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Multiple sclerosis; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Polymorphism, Genetic - genetics; Sphingosine 1 Phosphate Receptor Modulators - administration & dosage; Sphingosine 1 Phosphate Receptor Modulators - pharmacokinetics; Studies; Young Adult; United States > US
• DOI: 10.1007/s40262-018-0700-3
• ISSN: 0312-5963; 1179-1926

Objectives The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). Methods Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2–19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects ( n  = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1–2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 ( n  = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. Results In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration ( C max ; from 31.2 to 34.0 ng/mL) and elimination half-life ( T ½ ; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in C max versus the CYP2C9*1/*1 genotype. The mean T ½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. Conclusions Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.