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

Abstract

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.

Drug Interactions Involving 17α‐Ethinylestradiol: Considerations Beyond Cytochrome P450 3A Induction and Inhibition

“…Evidently, DDIs with combination OCs are well-documented and the topic remains of interest to the pharmaceutical industry and regulators. [4][5][6] For example, a significant number of study entries are available for OCs (DDI victim, N = 266; DDI perpetrator, N = 68) in the University of Washington Drug Interaction Solutions PK-based Drug Interaction Database (Tables S7 and S8; https://www.drugi ntera ction solut ions.org). As might be expected, there is considerable focus on gut and liver CYP3A4/5 as the loci of OC DDI.…”

“…With the widespread use of low‐dose combination (estrogen plus progestin) oral contraceptives (OCs), it is not surprising that their involvement in drug‐drug interactions (DDIs) has been studied extensively over the years 1–3 . In particular, investigators and regulators have sought to establish DDI study designs and more recently the US Food and Drug Administration has issued a draft guidance document on the topic 4–6 …”

“…There are additional considerations from the standpoint of OC study design. For example, what brand of OC is to be used in the DDI study? 4,71 Such a decision is not trivial, because it has been known for some time that the PK of EE itself is differentially impacted by the progestin used in the OC formulation. For example, EE serum levels are ~ 70% higher with gestodene (vs. desogestrel) 72 .…”

“…[1][2][3] In particular, investigators and regulators have sought to establish DDI study designs and more recently the US Food and Drug Administration has issued a draft guidance document on the topic. [4][5][6] When it comes to DDI involving OCs, cytochrome P450 (CYP) 3A (CYP3A) induction and inhibition looms large as it applies to both 17α-ethinylestradiol (EE) and co-formulated progestins. 3,7 For example, CYP3A4 is known to catalyze EE 2-hydroxylation and is expressed in the gut and liver.…”

Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy

“…In general, CYP inhibition is commonly known to elevate the blood level of concomitant drugs, which can result in serious adverse reactions to the medications ( Markoula et al, 2014 ; Sun et al, 2020 ). In contrast, CYP induction with combination therapy could cause decreased levels of drug in the blood, often reducing drug efficacy ( Markoula et al, 2014 ; Sun et al, 2020 ); although, not much is known about the pharmacodynamic consequences elicited by interactions between CYP inducers and substrates.…”