Development of a Translational Exposure-Bracketing Approach to Streamline the Development of Hormonal Contraceptive Drug Products

Clin Pharmacol Ther. 2022 Jun 20. doi: 10.1002/cpt.2690. Online ahead of print.ABSTRACTWorldwide, 922 million women of reproductive age (or their partners) use some sort of contraception to prevent pregnancy. Oral combined hormonal contraceptives (CHC) typically utilize a combination of a progestin and an estrogen. CHC are potentially at risk to metabolic drug-drug interaction (DDI) via CYP3A4, the main enzyme involved in the oxidative metabolism of ethinyl estradiol (EE) and most progestins, e.g. levonorgestrel (LNG) and drospirenone (DRSP). Recently, the 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 (fmCYP3A4 ), it would be of clinical benefit to determine if all progestins are at the same risk to CYP3A4-mediated metabolic DDI. LNG and DRSP are commonly used progestins that are at the margins of the rifampicin induction effect observed in vivo since they have the relatively lowest and highest fmCYP3A4 among commonly used CHC formulations containing norgestimate, desogestrel, norgestrel, and norethindrone. Therefore, we applied a multi-pronged strategy, i.e. (1) development of the PBPK models, (2) comparison of the effect of CYP3A inducers and inhibitors on DRSP vs. LNG, and (3) providing the clinical-practice context based on real world data, to explore ...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research