Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling. Methods Ex vivo placenta perfusions were performed in a closed–closed configuration, in both maternal-to-fetal and fetal-to-maternal directions ( n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration ( C trough ) values were compared with the target (0.23 mg/L) derived from in vivo exposure–response analysis. Results A decrease of 55% in maternal doravirine area under the plasma concentration–time curve (AUC) 0–24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure. Conclusion 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. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01127-0.
IntroductionDoravirine 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.MethodsAn 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.ResultsPerfusion 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.ConclusionsSubstantially 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.
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