Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects.
Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects.
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DOI：
10.1007/s11095-017-2153-z
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发表时间：
2017-08
影响因子：
3.7
通讯作者：
Sugiyama Y
中科院分区：
文献类型：
--
作者：
Toshimoto K;Tomaru A;Hosokawa M;Sugiyama Y
由于伊立替康的各种遗传多态性与副作用之间存在许多有争议的关联，因此利用基于计算机的虚拟临床研究（VCS）建立基于生理的药代动力学（PBPK）模型来分析与伊立替康副作用相关的因素。为了优化伊立替康及其代谢物在PBPK模型中的生化参数，引入了聚类牛顿法。在VCS中，考虑到酶和转运体的个体间变异性和遗传多态性，虚拟患者被生成。大约30组PBPK模型参数很好地再现了伊立替康及其代谢物的药代动力学。其中有19组较好地描述了UGT1A1 *28和SLCO1B1 C . 521t >C多态性对SN-38血药浓度、中性粒细胞减少和腹泻的影响，主要由Teft等报道（Br J Cancer. 112(5):857-65,）。VCS还显示胆道指数与腹泻显著相关的频率高于UGT1A1 *28多态性。VCS证实了UGT1A1 *28和SLCO1B1 C . 521t >C遗传多态性在伊立替康诱导的副作用中的重要性。VCS还表明，与UGT1A1 *28多态性相比，胆道指数是更好的腹泻生物标志物。本文的在线版本（doi:10.1007/s11095-017-2153-z）包含补充资料，仅供授权用户使用。
To establish a physiologically-based pharmacokinetic (PBPK) model for analyzing the factors associated with side effects of irinotecan by using a computer-based virtual clinical study (VCS) because many controversial associations between various genetic polymorphisms and side effects of irinotecan have been reported. To optimize biochemical parameters of irinotecan and its metabolites in the PBPK modeling, a Cluster Newton method was introduced. In the VCS, virtual patients were generated considering the inter-individual variability and genetic polymorphisms of enzymes and transporters. Approximately 30 sets of parameters of the PBPK model gave good reproduction of the pharmacokinetics of irinotecan and its metabolites. Of these, 19 sets gave relatively good description of the effect of UGT1A1 *28 and SLCO1B1 c.521T>C polymorphism on the SN-38 plasma concentration, neutropenia, and diarrhea observed in clinical studies reported mainly by Teft et al. (Br J Cancer. 112(5):857-65,). VCS also indicated that the frequency of significant association of biliary index with diarrhea was higher than that of UGT1A1 *28 polymorphism. The VCS confirmed the importance of genetic polymorphisms of UGT1A1 *28 and SLCO1B1 c.521T>C in the irinotecan induced side effects. The VCS also indicated that biliary index is a better biomarker of diarrhea than UGT1A1 *28 polymorphism. The online version of this article (doi:10.1007/s11095-017-2153-z) contains supplementary material, which is available to authorized users.