Development and Evaluation of Ontogeny Functions of the Major UDP-Glucuronosyltransferase Enzymes to Underwrite Physiologically Based Pharmacokinetic Modeling in Pediatric Populations.

Autor: Farhan N; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California, USA., Dahal UP; Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California, USA., Wahlstrom J; Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2024 Oct; Vol. 64 (10), pp. 1222-1235. Date of Electronic Publication: 2024 Jun 19.
DOI: 10.1002/jcph.2484
Abstrakt: Uridine 5'-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported. However, those ontogeny functions are based on in vitro data (i.e., enzyme abundance, in vitro substrate activity, and so on) and therefore, may not translate to in vivo maturation of UGTs in the clinical setting. This report describes meta-analysis of the literature to develop and compare ontogeny functions for 8 primary UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) based on published in vitro and in vivo studies. Once integrated with physiologically based pharmacokinetics modeling models, in vivo activity-based ontogeny functions demonstrated somewhat greater prediction accuracy (mean squared error, MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based ontogeny functions (MSE: 0.129).
(© 2024, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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