作者
Trevor N Johnson, Eleanor M Howgate, Saskia N de Wildt, Mark A Turner, Karen Rowland Yeo
发表日期
2023/8/1
期刊
Drug Metabolism and Disposition
卷号
51
期号
8
页码范围
1035-1045
出版商
American Society for Pharmacology and Experimental Therapeutics
简介
Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study, a midazolam and 1-hydroxymidazolam physiologically based pharmacokinetic model (PBPK) model was developed and used to define the ontogeny for hepatic cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyl transferase (UGT) 2B4. Data for model development and pharmacokinetic studies on intravenous midazolam in adults and pediatrics were collated from the literature. The PBPK model was verified in the adult population and then used to compare the performance of two ontogeny profiles for CYP3A4 in terms of parent drug elimination in pediatrics. Four studies also published data on the 1-hydroxymidazolam, and this was used to evaluate the known ontogeny for UGT2B4.For …
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