Physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2023-12-08 DOI:10.1007/s12272-023-01472-z
Chang-Keun Cho, Pureum Kang, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee, Chang-Ik Choi
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Abstract

Irbesartan, a potent and selective angiotensin II type-1 (AT1) receptor blocker (ARB), is one of the representative medications for the treatment of hypertension. Cytochrome P450 (CYP) 2C9 is primarily involved in the oxidation of irbesartan. CYP2C9 is highly polymorphic, and genetic polymorphism of this enzyme is the leading cause of significant alterations in the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes. The irbesartan PBPK model was established using the PK-Sim® software. Our previously reported pharmacogenomic data for irbesartan was leveraged in the development of the PBPK model and collected clinical pharmacokinetic data for irbesartan was used for the validation of the model. Physicochemical and ADME properties of irbesartan were obtained from previously reported data, predicted by the modeling software, or optimized to fit the observed plasma concentration–time profiles. Model evaluation was performed by comparing the predicted plasma concentration–time profiles and pharmacokinetic parameters to the observed results. Predicted plasma concentration–time profiles were visually similar to observed profiles. Predicted AUCinf in CYP2C9*1/*3 and CYP2C9*1/*13 genotypes were increased by 1.54- and 1.62-fold compared to CYP2C9*1/*1 genotype, respectively. All fold error values for AUC and Cmax in non-genotyped and CYP2C9 genotyped models were within the two-fold error criterion. We properly established the PBPK model of irbesartan in different CYP2C9 genotypes. It can be used to predict the pharmacokinetics of irbesartan for personalized pharmacotherapy in individuals of various races, ages, and CYP2C9 genotypes.

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基于生理学的药代动力学(PBPK)模型预测不同 CYP2C9 基因型的厄贝沙坦药代动力学
厄贝沙坦是一种强效、选择性血管紧张素 II 1 型(AT1)受体阻断剂(ARB),是治疗高血压的代表性药物之一。细胞色素 P450(CYP)2C9 主要参与厄贝沙坦的氧化。CYP2C9 具有高度多态性,该酶的遗传多态性是导致厄贝沙坦药代动力学显著改变的主要原因。本研究旨在建立基于生理学的药代动力学(PBPK)模型,以预测不同 CYP2C9 基因型的厄贝沙坦药代动力学。厄贝沙坦 PBPK 模型是利用 PK-Sim® 软件建立的。在建立 PBPK 模型的过程中,利用了我们先前报告的厄贝沙坦药物基因组学数据,并利用收集的厄贝沙坦临床药代动力学数据对模型进行了验证。厄贝沙坦的理化和 ADME 特性来自于先前报告的数据、建模软件的预测或优化,以适应观察到的血浆浓度-时间曲线。通过比较预测的血浆浓度-时间曲线和药代动力学参数与观察结果,对模型进行评估。预测的血浆浓度-时间曲线与观察到的曲线直观相似。与 CYP2C9*1/*1 基因型相比,CYP2C9*1/*3 和 CYP2C9*1/*13 基因型的预测 AUCinf 分别增加了 1.54 倍和 1.62 倍。在非基因分型和 CYP2C9 基因分型模型中,AUC 和 Cmax 的所有折合误差值均在两倍误差标准之内。我们正确地建立了不同 CYP2C9 基因型厄贝沙坦的 PBPK 模型。该模型可用于预测不同种族、年龄和 CYP2C9 基因型个体的厄贝沙坦药代动力学,以实现个性化药物治疗。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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