Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

Abstract

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.

Population pharmacokinetic analysis of doravirine in real‐world people with HIV

“…Doravirine TDM is certainly not to recommend routinely in PWH. However, despite limited clinical validation, it may be of particular relevance during pregnancy 24 or in patients receiving haemodialysis 25 or developing hepatic impairment. Furthermore, TDM can be useful to detect individuals with poor adherence who are exposed to a low level, thereby increasing the risk of developing viral resistance.…”

Drug exposure during pregnancy: Current understanding and approaches to measure maternal-fetal drug exposure

“…These models build on existing information and data to describe maternal-fetal drug transfer throughout pregnancy. There is an increasing focus on methodologies for including placental transfer physiology to describe fetal exposure ( De Sousa Mendes et al, 2017 ; Zhang et al, 2017 ; Zhang et al, 2018 ; George et al, 2020 ; Liu et al, 2020 ; Mian et al, 2020 ; Gingrich et al, 2021 ; Abduljalil et al, 2022a ; Bukkems et al, 2022 ; Peng et al, 2022 ). Methodologies capitalize on available in vitro , in vivo , and ex vivo studies in animals and humans to inform models for fetal exposure.…”

The impact of obesity on doravirine exposure in people with HIV

“…Blood samples for doravirine measurement were collected at the end of the dosing interval (24 AE 4 h) to assess doravirine C trough . Plasma samples were stored at À40 8C and were analysed in batch using a validated bioanalytical method [5].…”