Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

Autor: Hunt JP; University of Utah, Salt Lake City, Utah, USA., Dubinsky S; University of Waterloo, Waterloo, Ontario, Canada., McKnite AM; University of Utah, Salt Lake City, Utah, USA., Cheung KWK; Genentech, Inc., South San Francisco, California, USA., van Groen BD; Roche Pharma and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland., Giacomini KM; UCSF, San Francisco, California, USA., de Wildt SN; Erasmus MC, Rotterdam, The Netherlands.; Radboud University, Nijmegen, The Netherlands., Edginton AN; University of Waterloo, Waterloo, Ontario, Canada., Watt KM; University of Utah, Salt Lake City, Utah, USA.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Apr; Vol. 13 (4), pp. 576-588. Date of Electronic Publication: 2024 Jan 10.
DOI: 10.1002/psp4.13102
Abstrakt: Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5-95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K. Profiles for OAT3, P-gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5-95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population-specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.
(© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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