Background and Objective
Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal medications. Our objective was to develop and evaluate a novel, physiologically based pharmacokinetic modeling workflow for predicting perinatal and postnatal disposition of commonly used antiretroviral drugs administered prenatally to pregnant women living with human immunodeficiency virus.
Using previously published, maternal-fetal, physiologically based pharmacokinetic models for emtricitabine, dolutegravir, and raltegravir built with PK-Sim/MoBi®, placental drug transfer was predicted in late pregnancy. The total drug amount in fetal compartments at term delivery was estimated and subsequently integrated as initial conditions in different tissues of a whole-body, neonatal, physiologically based pharmacokinetic model to predict drug concentrations in the neonatal elimination phase after birth. Neonatal elimination processes were parameterized according to published data. Model performance was assessed by clinical data.
Neonatal physiologically based pharmacokinetic models generally captured the initial plasma concentrations after delivery but underestimated concentrations in the terminal phase. The mean percentage error for predicted plasma concentrations was − 71.5%, − 33.8%, and 76.7% for emtricitabine, dolutegravir, and raltegravir, respectively. A sensitivity analysis suggested that the activity of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 during the first postnatal days in term newborns is ~11% and ~30% of that in adults, respectively.
These findings demonstrate the general feasibility of applying physiologically based pharmacokinetic models to predict washout concentrations of transplacentally acquired drugs in newborns. These models can increase the understanding of pharmacokinetics during the first postnatal days and allow the prediction of drug exposure in this vulnerable population.
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Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health, all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The NIH awards numbers 5T32HD087969-03 and 5T32HD087969-02 also support this project.
Conflicts of interest/Competing Interests
Xiaomei I. Liu, Jeremiah D. Momper, Natella Y. Rakhmanina, Dionna J. Green, Gilbert J. Burckart, Tim R. Cressey, Mark Mirochnick, Brookie M. Best, John N. van den Anker, and André Dallmann have no conflicts of interest with respect to the research, authorship, and/or publication of this article. André Dallmann is an employee of Bayer AG, a company that is part of the Open Systems Pharmacology member team and involved in the Open Systems Pharmacology software development used in this study. The results from this study will be presented in part at the American College of Clinical Pharmacology Annual Meeting, September 2020.
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Liu, X.I., Momper, J.D., Rakhmanina, N.Y. et al. Physiologically Based Pharmacokinetic Modeling Framework to Predict Neonatal Pharmacokinetics of Transplacentally Acquired Emtricitabine, Dolutegravir, and Raltegravir. Clin Pharmacokinet (2021). https://doi.org/10.1007/s40262-020-00977-w