Development and Evaluation of Ontogeny Functions of the Major UDP-Glucuronosyltransferase Enzymes to Underwrite
Nashid Farhan1, Upendra P Dahal1, Jan Wahlstrom2
1Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California, USA.
Insights
Developing accurate pediatric drug dosing requires understanding age-dependent UGT maturation. New in vivo activity-based ontogeny functions improve pharmacokinetic predictions compared to in vitro models.
Area of Science:
- Pharmacology
- Drug Metabolism
- Pediatric Pharmacokinetics
Background:
- Uridine 5'-diphospho-glucuronosyltransferases (UGTs) exhibit variable expression in children.
- Accurate pediatric pharmacokinetics (PK) prediction necessitates understanding age-dependent UGT maturation for glucuronidated drugs.
Purpose of the Study:
- To develop and compare ontogeny functions for 8 major UGTs using a meta-analysis of in vitro and in vivo data.
- To evaluate the predictive accuracy of different ontogeny function types within physiologically based pharmacokinetic (PBPK) models.
Main Methods:
- Conducted a meta-analysis of published literature on UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, UGT2B17).
- Developed in vitro abundance-based, in vitro activity-based, and in vivo activity-based ontogeny functions.
- Integrated these functions into PBPK models to assess prediction accuracy.
Main Results:
- In vivo activity-based ontogeny functions showed improved prediction accuracy (MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based functions (MSE: 0.129).
- This suggests in vivo data provides a more reliable basis for pediatric UGT maturation modeling.
Conclusions:
- In vivo activity-based ontogeny functions are superior for predicting pediatric UGT maturation and PK.
- These findings can enhance the accuracy of pediatric drug dosing and safety assessments.
Abstract:
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).
