Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes.
PURPOSE
To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole.


METHODS
This was an open-label study in healthy subjects (aged 18-50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects received siponimod 0.25-mg single dose in treatment period 1 (days 1-14), itraconazole 100 mg twice daily in treatment period 2 (days 15-18), and siponimod 0.25-mg single dose (day 19) with itraconazole until day 31 (cohort 1) or day 35 (cohort 2) in treatment period 3. PK of siponimod alone and with itraconazole and safety were assessed.


RESULTS
Overall, 29/30 subjects completed the study. In treatment period 1, geometric mean AUCinf, T1/2, and median Tmax were higher while systemic clearance was lower in cohort 2 than cohort 1. In treatment period 3, siponimod AUC decreased by 10% (geo-mean ratio [90% confidence intervals]: 0.90 [0.84; 0.96]) and 24% (0.76 [0.69; 0.82]) in cohorts 1 and 2, respectively. Siponimod Cmax was similar between treatment periods 1 and 3. In both cohorts, the Cmax and AUC of the metabolites (M17, M3, and M5) decreased in the presence of itraconazole. All adverse events were mild.


CONCLUSIONS
The minor albeit significant reduction in plasma exposure of siponimod and its metabolites by itraconazole was unexpected. While the reason is unclear, the results suggest that coadministration of the two drugs would not cause a considerable increase of siponimod exposure independent of CYP2C9 genotype.
['Gardin|Anne|A|', 'Shakeri-Nejad|Kasra|K|', 'Feller|Andrea|A|', 'Huth|Felix|F|', 'Neelakantham|Srikanth|S|', 'Dumitras|Swati|S|']
D000293:Adolescent D000328:Adult D019540:Area Under Curve D001384:Azetidines D001593:Benzyl Compounds D065729:Cytochrome P-450 CYP2C9 D051544:Cytochrome P-450 CYP3A D065692:Cytochrome P-450 CYP3A Inhibitors D004347:Drug Interactions D004562:Electrocardiography D005260:Female D005838:Genotype D064368:Healthy Volunteers D006801:Humans D017964:Itraconazole D018655:Lymphocyte Count D008297:Male D008875:Middle Aged D000081243:Sphingosine 1 Phosphate Receptor Modulators D055815:Young Adult
Siponimod Pharmacokinetics Itraconazole Healthy subjects Drug-drug interactions