Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects.

Abstract

To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects. This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2mg over 5days (Days 1-6) followed by 2mg once daily on days 7-12. In Period 2, siponimod 2mg qd was co-administered with rifampin 600mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC). Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6ng/mL) was achieved in 4h (median Tmax,ss; range, 1.58-8.00) and the geometric mean AUCtau,ss was 546h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7ng/mL and 235h × ng/mL, respectively; median Tmax remained unchanged (4h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L. The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.