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

J Porter Hunt1, Samuel Dubinsky2, Autumn M McKnite1

  • 1University of Utah, Salt Lake City, Utah, USA.

CPT: Pharmacometrics & Systems Pharmacology
|December 29, 2023
PubMed

Insights

Pediatric physiologically-based pharmacokinetic (PBPK) models now include renal transporter (RT) ontogeny profiles. These novel profiles improve predictions of drug disposition in neonates and infants, enabling optimized pediatric dosing.

Area of Science:

  • Pharmacology
  • Pediatric Drug Development
  • Renal Physiology

Background:

  • Optimal drug dosing in infants requires understanding renal transporter (RT) activity, which changes with maturation.
  • Pediatric physiologically-based pharmacokinetic (PBPK) models need accurate RT ontogeny profiles, especially for neonates, to predict drug disposition.

Purpose of the Study:

  • To develop and validate novel ontogeny profiles for key renal transporters in the pediatric population.
  • To improve the accuracy of pediatric PBPK models for predicting drug pharmacokinetics in infants and neonates.

Main Methods:

  • RT expression data from human kidney samples were used to estimate ontogeny profiles via maximum likelihood estimation.
  • PBPK models for four RT substrates (acyclovir, ciprofloxacin, furosemide, meropenem) were evaluated with and without the novel ontogeny profiles.
  • Model performance was assessed using average fold error (AFE), absolute average fold error (AAFE), and the proportion of observations within the 5-95% prediction interval.

Main Results:

  • Novel maximum likelihood profiles were estimated for OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K.
  • Inclusion of OAT3, P-gp, and MATE1 ontogeny profiles significantly improved PBPK model accuracy for infant furosemide and neonatal meropenem.
  • Model performance for neonatal ciprofloxacin simulations improved, with the percent of data within the 5-95% prediction interval increasing from 48% to 98%.

Conclusions:

  • Novel RT ontogeny profiles substantially enhance the performance of neonatal PBPK models.
  • These validated estimates of maturational differences in RT activity are crucial for optimizing drug dosing in pediatric populations.
  • The developed profiles provide a valuable tool for precise drug therapy in infants and children.

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