A drug-drug interaction study to evaluate the effects of strong CYP3A4 inducer on the pharmacokinetics of segesterone acetate and ethinyl estradiol in a contraceptive vaginal system

In 2018, the US FDA approved a long-acting contraceptive vaginal system (CVS) releasing a new progestin, segesterone acetate (SA) and ethinyl estradiol (EE). As most progestins and EE used in hormonal contraceptives are metabolized via the CYP3A4 pathway, drug-drug interactions within the CYP3A4 network are a potential concern for contraceptive efficacy and/or safety. SA and EE systemic exposure could be reduced following administration of a strong CYP3A4 inducer such as rifampin, thus influencing risk of pregnancy or side effects. The study aimed to assess the pharmacokinetics of SA and EE from the CVS in healthy women when co-administered with rifampin. This randomized, open-label, cross-over study was conducted at two Canadian sites to evaluate potential drug-drug interaction between rifampin (600 mg once daily) and the CVS releasing on average 150 µg of SA and 13 µg of EE daily. Blood samples were collected at predetermined time intervals after CVS insertion with and without concomitant Rifampin treatment. Serum concentrations of SA and EE were measured by validated LCMS/MS method. Concentrations were used to calculate pharmacokinetic parameters for comparison. Twenty-one healthy women were enrolled and randomized (1:1) to sequence A (CVS alone in treatment cycle 1; CVS + rifampin in treatment cycle 2) or sequence B (CVS + rifampin in treatment cycle 1; CVS alone in treatment cycle 2); 18 women completed the study. Rifampin co-treatment had no significant impact on PK parameters of SA. The 90% confidence intervals of geometric mean ratios (GMR) for AUC and Cmax were wholly contained within 0.8–1.25, supportive of bioequivalence. Serum concentrations of EE were significantly decreased: the GMR and 90% confidence intervals for AUC were 0.44 (0.39–0.50) and Cmax was 0.55 (0.47–0.65). No new or unexpected safety concerns were observed during the study conduct. We report a drug-drug interaction of rifampin on systemic exposure of EE but not SA. As the progestin seems to be the major driver of contraceptive efficacy, we do not expect co-administration of a CYP3A4 inducer to reduce contraceptive effectiveness. These results suggest that this CVS may be used with rifampin without additional precautions to prevent unintended pregnancy. This trial was registered with ClincalTrials.gov Identifier NCT04290390.