PBPK modeling to predict the pharmacokinetics of pantoprazole in different CYP2C19 genotypes

초록

Pantoprazole is used to treat gastroesophageal refl ux disease (GERD), maintain healing of erosive esophagitis (EE), andcontrol 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 geneticpolymorphism aff ects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establishthe physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populationswith various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases wasconducted 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 plasmaconcentration–time profi les and/or pharmacokinetic parameters (AUC and C max ) with the clinical observation results. Thepredicted plasma concentration–time profi les in diff erent CYP2C19 phenotypes properly captured the observed profi les. All fold error values for AUC and C max were included in the two-fold range. Consequently, the minimal PBPK model forpantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokineticsof pantoprazole in diff erent CYP2C19 phenotypes. The present model can broaden the insight into the individualizedpharmacotherapy for pantoprazole.

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