The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam

Abstract

It is known that co‐administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono‐preparations or combined with ethinylestradiol. In a randomized clinical drug‐drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono‐products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12–14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15–37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57–90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone‐containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers—although it is acknowledged that the exact exposure‐response relationship for contraceptive efficacy is currently unclear for most progestins.

Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling

“…Overview of our PBPK modeling strategy. The simulated LNG fraction metabolized by CYP3A4 (fm CYP3A4 ) was verified by comparing to published clinical drug‐drug interaction (DDI) studies 16–18 . CHC, combined hormonal contraceptive; FDC, fixed‐dose combination; PBPK, physiologically‐based pharmacokinetic; SHBG, sex hormone binding globulin.…”

“…An additional model verification step was performed comparing predicted and observed AUC values for LNG, when administered as a combined contraceptive, with and without three different strong CYP3A4 inducers (carbamazepine, rifampicin, and efavirenz). An E max function was implemented to the rifampicin PBPK model, to account for the observed stimulatory effect of rifampicin on SHBG concentrations of approximately twofold 18 . Available verified perpetrator models of efavirenz (https://github.com/Open-Systems-Pharmacology/Efavirenz-Model/releases) and rifampin (https://github.com/Open-Systems-Pharmacology/Rifampicin-Model/releases) were used to predict DDIs.…”

“…Model development and verification was performed using a step-wise approach (Figure 1). The simulated LNG fraction metabolized by CYP3A4 (fm CYP3A4 ) was verified by comparing to published clinical DDI studies [16][17][18]. All model simulations, unless otherwise noted, utilized a virtual population of 20 females and mean PK metric values for simulation and verification purposes.…”

“…The aim of this study was to develop a PBPK framework to evaluate DDIs of oral hormonal contraceptives using LNG as the victim drug. Focusing on CYP3A4 as the major interacting pathway for CHCs, we developed PBPK models for LNG and its common comedication EE using previous DDI studies [16][17][18]. The PBPK platform for CHCs was then applied to investigate the impact of DDI on the PK of LNG in different clinically relevant scenarios.…”

“…Overview of our PBPK modeling strategy. The simulated LNG fraction metabolized by CYP3A4 (fm CYP3A4 ) was verified by comparing to published clinical drug-drug interaction (DDI) studies[16][17][18]. Sex Hormone Binding Globulin (SHBG), Fixed-Dose Combination (FDC), Combined Hormonal Contraceptive (CHC).…”