Effects of Ensitrelvir on the Pharmacokinetics of Combined Oral Contraceptives (Ethinyl Estradiol/Drospirenone) in Healthy Adult Women: A Phase 1 Fixed-Sequence, Multiple-Dose, Drug–Drug Interaction Study

Background and Objective Ensitrelvir has shown cytochrome P450 3A (CYP3A) inhibitory/induction potential in in vitro studies. This open-label, fixed-sequence Phase 1 study evaluated potential drug–drug interactions between ensitrelvir and a combined oral contraceptive (COC) containing ethinyl estradiol (EE) and drospirenone in healthy women of childbearing age. Methods Healthy premenopausal women received EE/drospirenone (0.02 mg/3 mg) on days 1–24. Ensitrelvir was co-administered on day 20 (375 mg) and days 21–24 (125 mg/day). Blood samples were collected on days 19, 20, and 24 to assess plasma EE, drospirenone, and ensitrelvir concentrations. The primary endpoint was evaluation of the maximum plasma concentration, time to maximum plasma concentration, and area under the plasma concentration-time curve over the dosing interval τ (AUC0–τ) assessed using noncompartmental methods. Treatment-emergent adverse events (TEAEs) were recorded for safety assessments. Results The safety and pharmacokinetic parameter population comprised 24 and 23 participants, respectively. Compared with day 19, AUC0–τ ratios on days 20 and 24 were 1.02- and 1.07-fold for EE and 1.10- and 1.80-fold for drospirenone, respectively. This result suggested the inhibitory potential for CYP3A to be likely weaker on the first day than on the last day. Ensitrelvir AUC0–τ was higher on day 24 versus day 20 and comparable with that reported previously. Treatment-emergent adverse events occurred in 58.3% of participants, none of which were severe, serious, or led to treatment discontinuation. Conclusion Ensitrelvir has no clinically meaningful effect on the pharmacokinetics of EE and drospirenone, and the combination was well tolerated. These findings support the co-administration of ensitrelvir with COCs in clinical practice. Trial Registration NCT06775730. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-026-01541-3.