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

Autor: Bukkems VE; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands. Vera.Bukkems@radboudumc.nl., van Hove H; Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Roelofsen D; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands.; Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Freriksen JJM; Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands., van Ewijk-Beneken Kolmer EWJ; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands., Burger DM; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands., van Drongelen J; Department of Obstetrics and Gynaecology, Radboud university medical center, Nijmegen, The Netherlands., Svensson EM; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands.; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Greupink R; Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Colbers A; Department of Pharmacy, Radboud Institute of Health Sciences (RIHS), Radboud university medical center, Nijmegen, the Netherlands.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2022 Aug; Vol. 61 (8), pp. 1129-1141. Date of Electronic Publication: 2022 May 17.
DOI: 10.1007/s40262-022-01127-0
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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