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Physiologically Based Pharmacokinetic Modeling Framework to Predict Neonatal Pharmacokinetics of Transplacentally Acquired Emtricitabine, Dolutegravir, and Raltegravir

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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.

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Fig. 1
Fig. 2

taken from an in vivo study of Hirt et al. [17], IMPAACT P1026 [10], and Clarke et al. [16]. a Emtricitabine 400-mg single dose in pregnant women with an average gestational age of 39 weeks at delivery. Empty circles represent individual concentration data in the maternal plasma taken from an in vivo study of Hirt et al. [17]; the line represents the predicted mean concentrations in the maternal plasma; the shaded area represents the predicted 5th–95th percentile range of the prediction. b Emtricitabine 400-mg single dose in pregnant women with an average gestational age of 39 weeks at delivery. Empty circles represent individual concentration data in the umbilical vein taken from an in vivo study of Hirt et al. [17] The line represents the predicted mean concentrations in the umbilical vein. The shaded area represents the predicted 5th–95th percentile range of the prediction. c Emtricitabine 400-mg single dose in pregnant women with an average gestational age of 39 weeks at delivery. The line represents the predicted mean amount of emtricitabine in the fetus. The marks represent the delivery time after the last dose. d Dolutegravir 50 mg once a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the maternal plasma taken from an in vivo study of IMPAACT P1026; [10] the line represents the predicted mean concentration in the maternal plasma; the shaded area represents the predicted 5th–95th percentile range of the prediction. e Dolutegravir 50 mg once a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the umbilical vein taken from an in vivo study of IMPAACT P1026; [10] the line represents the predicted mean concentration in the umbilical vein. The shaded area presents the predicted 5th–95th percentile range of the prediction. f Dolutegravir 50 mg once a day in pregnant women with an average gestational age of 38 weeks at delivery; the line represents the predicted mean amount of dolutegravir in the fetus. The marks represent the delivery time after the last dose. g Raltegravir 400 mg twice a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the maternal plasma taken from an in vivo study of Clarke et al. [16]; the line represents the predicted mean concentrations in the maternal plasma; the shaded area represents the predicted 5th–95th percentile range of the prediction. h Raltegravir 400 mg twice a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the umbilical vein taken from an in vivo study of Clarke et al. [16]; the line represents the predicted mean concentrations in the umbilical vein. The shaded area represents the predicted 5th–95th percentile range of the prediction. i Raltegravir 400 mg twice a day in pregnant women with an average gestational age of 38 weeks at delivery. The line represents the predicted mean amount of raltegravir in the fetus. The marks represent the delivery time after the last dose. conc concentration

Fig. 3

taken from Hirt et al. [17]. b Dolutegravir plasma concentration in newborns; maternal dose of 50 mg once a day. Observed data were taken from IMPAACT P1026 [10]. c Raltegravir plasma concentration in newborns; maternal dose of 400 mg twice a day. Observed data were taken from Clarke et al. [16] conc concentration

Fig. 4

taken from Hirt et al. [17] and black circles represent median observed data. b Emtricitabine plasma concentration in newborns with differing unbound fractions; maternal dose of 400 mg single dose. Empty circles represent observed data taken from Hirt et al. [17] and black circles represent median observed data. c Dolutegravir plasma concentration in newborns with differing uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 3A4 activities; maternal dose of 50 mg once a day. Empty circles represent observed data taken from IMPAACT P1026 [10] and black circles represent median observed data. d Dolutegravir plasma concentration in newborns with differing unbound fractions; maternal dose of 50 mg once a day. Empty circles represent observed data taken from IMPAACT P1026 [10] and black circles represent median observed data. e Raltegravir plasma concentration in newborns with differing uridine diphosphate glucuronosyltransferase 1A1 activity and renal elimination; maternal dose of 400 mg twice a day. Empty circles represent observed data taken from Clarke et al. [16] and black circles represent median observed data. f Raltegravir plasma concentration in newborns with differing unbound fractions; maternal dose of 50 mg once a day. Empty circles represent observed data taken from Clarke et al. [16] and black circles represent median observed data. conc concentration

Fig. 5

taken from Hirt et al. [17] and black circles represent median observed data. b Dolutegravir plasma concentration in newborns with differing dosing; maternal dose of 50 mg once a day. Empty circles represent observed data taken from IMPAACT P1026 [10] and black circles represent median observed data. c Raltegravir plasma concentration in newborns with differing dosing; maternal dose of 400 mg twice a day. Empty circles represent observed data taken from Clarke et al. [16] and black circles represent median observed data. conc concentration

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Children’s National Hospital, 10430 Owen Brown Road, Columbia, Maryland, 21044, USA

    Xiaomei I. Liu & John N. van den Anker

  2. Division of Infectious Diseases, Children’s National Hospital, Washington, DC, USA

    Xiaomei I. Liu & Natella Y. Rakhmanina

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA

    Jeremiah D. Momper & Brookie M. Best

  4. Pediatric Department, School of Medicine, Rady Children’s Hospital San Diego, La Jolla, CA, USA

    Jeremiah D. Momper & Brookie M. Best

  5. Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA

    Natella Y. Rakhmanina

  6. Office of Pediatric Therapeutics, US Food and Drug Administration, Silver Spring, MD, USA

    Dionna J. Green

  7. Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD, USA

    Gilbert J. Burckart

  8. PHPT/IRD 174, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand

    Tim R. Cressey

  9. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK

    Tim R. Cressey

  10. School of Medicine, Boston University, Boston, MA, USA

    Mark Mirochnick

  11. Division of Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, Switzerland

    John N. van den Anker

  12. Bayer AG, Clinical Pharmacometrics, Leverkusen, Germany

    André Dallmann

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  1. Xiaomei I. Liu
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Correspondence to Xiaomei I. Liu.

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Funding

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 60, 795–809 (2021). https://doi.org/10.1007/s40262-020-00977-w

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