The exposure to and efficacy of doravirine in pregnant women as assessed by physiologically-based pharmacokinetic modelling

Introduction Doravirine is currently not recommended for pregnant women living with HIV due to the lack of efficacy and safety data. Physiological changes during pregnancy can significantly decrease drug exposure, and, thereby, lower the efficacy. Awaiting clinical data, this study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically-based pharmacokinetic (PBPK) modelling. Methods An existing and validated three-compartment PBPK model of doravirine for a healthy, non-pregnant population was modified to a 18-compartment PBPK model using Simcyp Simulator V20. The permeability-limited placenta model was included in the extended PBPK model to study placental transfer to the fetus. To parameterize the placenta model, ex vivo human cotyledon perfusion experiments were performed, and a mechanistic model was developed to derive placental transfer constants. The final pregnancy PBPK model was used to predict the maternal and fetal geometric mean (GM) concentration at 24h after dosing (C24h) at 26, 32 and 40 weeks of pregnancy. The GM C24h was compared to the target derived from in vivo exposure-response analysis of 0.23 mg/L. Results Perfusion experiments showed that doravirine extensively crosses the placenta. In comparison to non-pregnant women, the final pregnancy PBPK model estimated a maternal decrease in GM C24h of 55% for 40 weeks pregnancy. All predicted maternal GM C24h were <0.23 mg/L. Conclusions Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine, and the use should preferentially be restricted to clinical trials.