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Special Populations (SPO)

Poster Session I

PT-001 - MAXIMUM LIKELIHOOD ESTIMATION OF RENAL TRANSPORTER ONTOGENY PROFILES FOR PEDIATRIC PBPK MODELING.

Wednesday, March 22, 2023
5:00 PM – 6:30 PM EDT
Presidential Trainee Recipient David J. Goldstein Trainee Award Recipient Top Poster Ribbon
P. Hunt1, S. Dubinsky2, A. McKnite1, K. Cheung3, B. van Groen4, K. Giacomini5, S. de Wildt6,7, A. Edginton2, K. Watt1; 1University of Utah, Salt Lake City, UT, USA, 2University of Waterloo, Waterloo, Ontario, Canada, 3Genentech, South San Francisco, CA, USA, 4Roche Innovation Center Basel, Basel, Switzerland, 5University of California, San Francisco, San Francisco, CA, USA, 6Radboud University Medical Center, Nijmegen, The Netherlands, 7Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.

    Presenting Author(s)

  • Porter Hunt, PhD

    Postdoctoral Fellow
    University of Utah
    Salt Lake City, Utah, United States



Background: Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Ontogeny profiles for RT activity in infants are needed to inform physiologically based pharmacokinetic (PBPK) models to determine optimal treatment.

Methods: Human kidney postmortem cortical tissue samples spanning the pediatric age spectrum were obtained from biobanks in the US and the Netherlands. Normalized RT expression measurements from these samples represented a fraction of mature RT activity. Maximum likelihood estimated the distributions of RT activity across the pediatric ages, including preterm and term neonates. PBPK models of three drugs that are RT substrates were evaluated with and without ontogeny profiles using combined absolute average fold error (AAFE) and percent of data within the 5% to 95% prediction interval.

Results: Ontogeny profiles are represented in Figure 1 for 10 RTs. The ontogeny profile for OAT3 improved furosemide and meropenem infant PBPK model AAFE from 11.41 to 1.45 and 2.51 to 1.23, respectively, and improved percent of ciprofloxacin data from 45% to 96%.

Conclusion: These novel RT ontogeny profiles provide reliable estimates of maturational differences in RT activity to inform PBPK models for optimal dosing in children.

Cheung, K. W. K. et al. A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization. Clin. Pharmacol. Ther. 106, 1083–1092 (2019).

Figure 1: A. Renal transporter ontogeny profiles. Observed data from neonates and PBPK model output for B. Meropenem; C. Ciprofloxacin; D. Furosemide.