Xiaomei I Liu1,2, Jeremiah D Momper3,4, Natella Y Rakhmanina5,6, Dionna J Green7, Gilbert J Burckart8, Tim R Cressey9,10, Mark Mirochnick11, Brookie M Best3,4, John N van den Anker12,13, André Dallmann14. 1. Division of Clinical Pharmacology, Children's National Hospital, 10430 Owen Brown Road, Columbia, Maryland, 21044, USA. rph5862@gmail.com. 2. Division of Infectious Diseases, Children's National Hospital, Washington, DC, USA. rph5862@gmail.com. 3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA. 4. Pediatric Department, School of Medicine, Rady Children's Hospital San Diego, La Jolla, CA, USA. 5. Division of Infectious Diseases, Children's National Hospital, Washington, DC, USA. 6. Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA. 7. Office of Pediatric Therapeutics, US Food and Drug Administration, Silver Spring, MD, USA. 8. Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD, USA. 9. PHPT/IRD 174, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand. 10. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. 11. School of Medicine, Boston University, Boston, MA, USA. 12. Division of Clinical Pharmacology, Children's National Hospital, 10430 Owen Brown Road, Columbia, Maryland, 21044, USA. 13. Division of Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland. 14. Bayer AG, Clinical Pharmacometrics, Leverkusen, Germany.
Abstract
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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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