Cho Chang-Keun, Ko Eunvin, Mo Ju Yeon, Kang Pureum, Jang Choon-Gon, Lee Seok-Yong, Lee Yun Jeong, Bae Jung-Woo, Choi Chang-Ik
School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea.
Arch Pharm Res. 2024 Jan;47(1):82-94. doi: 10.1007/s12272-023-01478-7. Epub 2023 Dec 27.
Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison syndrome (ZES). Pantoprazole is mainly metabolized by cytochrome P450 (CYP) 2C19, converting to 4'-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the genetic polymorphism affects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populations with various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases was conducted to collect the clinical pharmacogenomic data, physicochemical data, and disposition properties of pantoprazole, and the collected data were used for model establishment. The model was evaluated by comparing the predicted plasma concentration-time profiles and/or pharmacokinetic parameters (AUC and C) with the clinical observation results. The predicted plasma concentration-time profiles in different CYP2C19 phenotypes properly captured the observed profiles. All fold error values for AUC and C were included in the two-fold range. Consequently, the minimal PBPK model for pantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokinetics of pantoprazole in different CYP2C19 phenotypes. The present model can broaden the insight into the individualized pharmacotherapy for pantoprazole.
泮托拉唑用于治疗胃食管反流病（GERD）、维持糜烂性食管炎（EE）的愈合以及控制与卓-艾综合征（ZES）相关的症状。泮托拉唑主要通过细胞色素P450（CYP）2C19代谢，转化为4'-去甲基泮托拉唑。CYP2C19是一种具有遗传多态性的酶，其遗传多态性会影响泮托拉唑的药代动力学和/或药效动力学。在本研究中，我们旨在建立基于生理的药代动力学（PBPK）模型，以预测泮托拉唑在具有不同CYP2C19代谢活性人群中的药代动力学。我们对既往报告和药物数据库进行了全面调查，以收集泮托拉唑的临床药物基因组学数据、理化数据和处置特性，并将收集到的数据用于模型建立。通过将预测的血浆浓度-时间曲线和/或药代动力学参数（AUC和C）与临床观察结果进行比较来评估该模型。不同CYP2C19表型的预测血浆浓度-时间曲线能够恰当地反映观察到的曲线。AUC和C的所有倍差误差值均在两倍范围内。因此，与CYP2C19基因多态性相关的泮托拉唑最小PBPK模型得以正确建立，并且它可以预测泮托拉唑在不同CYP2C19表型中的药代动力学。本模型可以拓宽对泮托拉唑个体化药物治疗的认识。
