Quantitative assessment of levonorgestrel binding partner interplay and drug-drug interactions using physiologically based pharmacokinetic modeling.

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically co-formulated 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 sub-optimal 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/m2 ) 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.