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

Abstract

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4-mediated metabolism, there is concern regarding drug-drug interactions (DDI), particularly a suboptimal LNG exposure when co-administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically based pharmacokinetic (PBPK) model for LNG in PK-Sim (v8.0) accounting for the impact of EE and BMI on LNG's binding to sex-hormone binding globulin (SHBG). Model parameters were optimized following intravenous and oral administration of 0.09 mg LNG. The combined LNG-EE PBPK model was verified regarding CYP3A4-mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI≥30kg/m 2) with and without coadministration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism-based CYP3A4 inhibitor). Total and free LNG exposures, when co-administered with EE, decreased 2-fold in the presence of rifampin, whereas they increased 1.5-fold in the presence of itraconazole. While changes in total and unbound exposure were decreased in obese women compared to normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups.

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

“…), resulted in a decrease in the area under curve (AUC) of LNG by ~ 50%. 11 This decrease in total LNG exposure was more pronounced in the presence of rifampicin in obese women (BMI ≥ 30 kg/m 2 ) compared with women with a BMI < 25 kg/m 2 . However, due to ethical concerns there are no clinical trials that evaluate the combined impact of BMI, SHBG, and CYP3A inducers on the exposure-response relationship of HCs in general and LNG in particular.…”

“…Whereas DRSP represents the upper limit of fm CYP3A4 (62%), LNG covers the low to intermediate range with fm CYP3A4 of 33%. 10,11 In order to determine the impact of DDIs and other extrinsic/intrinsic factors on the exposure and efficacy of HCs with different fm CYP3A4 , we used an exposure-based bracketing approach. The current analysis focuses on the lower limit case scenario (i.e., evaluating the impact of DDIs on LNG's exposure-response).…”

“…The back-calculated fm CYP3A4 for LNG only contraceptive was found to be 47%, whereas in combination with EE, LNG fm CYP3A4 is ~ 33%. 11 In addition to CYP3A4-mediated DDIs, the exposure of LNG in CHCs with EE is also affected by changes in drug distribution because of changes in protein-binding. LNG binds to both sex hormone binding globulin (SHBG; 48%) and albumin (50%), respectively.…”

“…Previously developed combined PBPK models of LNG, EE, and carbamazepine were used in the current analysis. 11 These LNG alone and combined LNG-EE models account for the binding of LNG to albumin and SHBG, while also incorporating the effect of EE and BMI on the concentrations of SHBG thereby the binding of LNG to SHBG. An maximum effect (E max ) function was used to account for the effect of EE on SHBG concentrations.…”

“…The effect of strong CYP3A4 inducers/inhibitors on the exposure of LNG and was evaluated in both women with BMI < 25 kg/m 2 and obese women (BMI ≥ 30 kg/m 2 ) using a PBPK model that also considered changes in SHBG concentrations and interactions among EE, SHBG, and LNG. 11 All simulations were conducted at steady-state after oral administration of LNG150 (LNG: 150 µg, EE: 30 µg) or LNG100 (LNG: 100 µg, EE: 20 µg) CHC pills with the following CYP3A4 inducers: RIF (100 mg q.d. ), carbamazepine (400 mg q.d.…”