Rodrigo Cristofoletti

Worldwide, 922 million women of reproductive age (or their partners) use some sort of contraception to prevent pregnancy. Oral combined hormonal contraceptives (CHCs) typically utilize a combination of a progestin and an estrogen. CHCs are potentially at risk to metabolic drug–drug interaction (DDI) via CYP3A4, the main enzyme involved in the oxidative metabolism of ethinyl estradiol and most progestins (e.g., levonorgestrel (LNG) and drospirenone (DRSP)). Recently, the US Food and Drug Administration (FDA) issued a guidance addressing metabolic DDIs in the realm of CHC, establishing an overall class‐based recommendation with respect to avoidance of CYP3A4 induction interactions. Given that different progestins have varying magnitudes of fraction metabolized by CYP3A4 (fm CYP3A4 ), it would be of clinical benefit to determine if all progestins are at the same risk to CYP3A4‐mediated metabolic DDIs. LNG and DRSP are commonly used progestins that are at the margins of the rifampicin induction effect observed in vivo because they have the relatively lowest and highest fm CYP3A4 among commonly used CHC formulations containing norgestimate, desogestrel, norgestrel, and norethindrone. Therefore, we applied a multi‐pronged strategy (i.e., (i) development of the physiologically‐based pharmacokinetic models; (ii) comparison of the effect of CYP3A inducers and inhibitors on DRSP vs. LNG; and (iii) providing the clinical‐practice context based on real‐world data, to explore the difference in DDI risk for oral CHCs.