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
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: 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. 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. 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. 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. NCT06775730. Ensitrelvir is an oral medicine used to treat coronavirus disease 2019 (COVID-19). It is also being reviewed by health authorities to determine whether it can help prevent COVID-19 infection after exposure to the virus. Women who may need this medicine might also take birth control pills, which usually contain two hormones, progestin and estrogen in the form of ethinyl estradiol (EE) and drospirenone (DRSP), respectively. Some medicines can change the levels of these synthetized hormones in the plasma, which can affect how well the medicine works or causes side effects. In this study, 24 healthy women took a common birth control pill every day for 24 days. From days 20 to 24, they also took ensitrelvir. Researchers measured EE and DRSP concentrations in the plasma before and after co-administration with ensitrelvir. The results showed that EE exposure did not change meaningfully when co-administered with ensitrelvir. Drospirenone exposure increased by up to about 80%, but it was still within a range that was considered safe. No serious side effects were reported. These findings suggest that ensitrelvir can be taken together with EE/DRSP birth control pills without dose adjustments and without increasing safety concerns. Although this study focused on EE/DRSP, the results are expected to apply to other commonly used birth control pill combinations (such as those containing levonorgestrel, norethindrone or etonogestrel), because they share similar metabolic pathways.
Source: Clinical Drug Investigation
Authors: Ryosuke Shimizu, Risa Yokokawa Shibata, Ryuji Kubota, Sho Okuda, Takuhiro Sonoyama
Institution: Shionogi (Japan)
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,190
Funder: Shionogi
OpenAlex ID: W7143665939