PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co‐Administered with CYP3A4 Inhibitors

CYP3A4型 基于生理学的药代动力学模型 药理学 药代动力学 代谢物 医学 伊曲康唑 化学 内科学 细胞色素P450 新陈代谢 抗真菌 皮肤病科
作者
Kenichi Umehara,Neil Parrott,Emilie Schindler,Valentin Legras,Georgina Meneses‐Lorente
出处
期刊:Clinical Pharmacology & Therapeutics [Wiley]
被引量:1
标识
DOI:10.1002/cpt.3386
摘要

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady‐state systemic exposure on co‐administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5–12.5 mg/kg and fluconazole at 3–12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co‐administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0− t ) was increased by approximately sevenfold and five to threefold by strong and high‐moderate and low‐moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.

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