Drug-Drug Interaction Studies With Oral Contraceptives: Pharmacokinetic/Pharmacodynamic and Study Design Considerations.

Oral contraceptives (OCs) are the most widely used form of birth control among women of childbearing potential. Knowledge of potential drug-drug interactions (DDIs) with OCs becomes imperative to provide information on the medication to women of childbearing potential and enable their inclusion in clinical trials, especially if the new molecular entity is a teratogen. Although a number of DDI guidance documents are available, they do not provide recommendations for the design and conduct of OC DDI studies. The evaluation of DDI potential of a new molecular entity and OCs is particularly challenging because of the availability of a wide variety of combinations of hormonal contraceptives, different doses of the ethinyl estradiol, and different metabolic profiles of the progestin component. The aim of this review is to comprehensively discuss factors to be considered such as pharmacokinetics (PK), pharmacodynamics (PD), choice of OC, and study population for the conduct of in vivo OC DDI studies. In this context, metabolic pathways of OCs, the effect of enzyme inhibitors and inducers, the role of sex hormone-binding globulin in the PK of progestins, current evidence on OC DDIs, and the interpretation of PD end points are reviewed. With the emergence of new tools like physiologically based PK modeling, the decision to conduct an in vivo study can be made with much more confidence. This review provides a comprehensive overview of various factors that need to be considered in designing OC DDI studies and recommends PK-based DDI studies with PK end points as adequate measures to establish clinical drug interaction and measurement of PD end points when there is basis for PD interaction.