Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta‐Analysis Approach

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug‐drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m 2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically‐based pharmacokinetic modeling and model‐based meta‐analysis approach to determine LNG’s efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG‐containing hormonal contraceptives (HCs). Based on this approach, co‐administration of strong CYP3A4 inducers and LNG‐containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m 2 : 50–65%; obese women: 70–75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2–1.30 and 1.80–2.10, respectively, in women with BMI < 25 kg/m 2 (incidence rate ratios (IRRs): 1.7–2.2), whereas it ranged from 1.6–1.80 and 2.40–2.85 in obese women (IRR: 2.2–3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.