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

Purpose: To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects.

Methods: This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45 years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1-6) followed by 2 mg once daily on days 7-12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [C], median time to achieve C [T], and area under the curve at steady state [AUC]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC).

Results: Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean C (28.6 ng/mL) was achieved in 4 h (median T; range, 1.58-8.00) and the geometric mean AUC was 546 h × ng/mL. In Period 2, the siponimod geometric mean C and AUC decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median T remained unchanged (4 h). Rifampin co-administration increased M3 C by 53% while M5 C remained unchanged. The AUC 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 × 10/L.

Conclusions: The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in C (45%) and AUC (57%) in healthy subjects.