Seok-Yong Lee, Chang-Keun Cho, Pureum Kang, Eunvin Ko and Chou Yen Mu
Journal of Pharmacology and Experimental Therapeutics June 2023, 385 (S3) 173; DOI: https://doi.org/10.1124/jpet.122.508580
Abstract
Introduction: Irbesartan, a potent and selective angiotensin II type-1 receptor blocker, is mainly metabolized through oxidation and glucuronide conjugation. Its oxidation is primarily mediated by CYP2C9, and the genetic polymorphism of CYP2C9 significantly affects the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model of irbesartan in different CYP2C9 genotypes for individualized pharmacotherapy with irbesartan according to the genotype of CYP2C9.
Methods: The irbesartan PBPK model was established using PK-Sim® in three different CYP2C9 genotypes (CYP2C91/1, 1/3, and 1/13). Our pharmacogenomic data of irbesartan and a total of 15 clinical pharmacokinetic data of irbesartan with different demographic characteristics and dose regimens were leveraged to develop and validate the model. Physicochemical and ADME properties of irbesartan were obtained from previously reported data or optimized to capture the plasma concentration-time profiles in different CYP2C9 genotypes.
Results: Predicted plasma concentration-time profiles were visually similar to the observed profiles in different CYP2C9 genotypes. The ranges of fold errors for AUCinf and Cmax in development were 1.01-1.09 and 0.92-1.02 respectively, which were strictly satisfied with the evaluation criterion. The ranges of fold errors for AUCinf and Cmax in single-dose validation were 0.53-1.87 and 0.61-1.90, respectively, and in multiple-dose validation were 0.87-1.64 and 0.77-1.82, respectively, which were also within the evaluation criterion.
Conclusion: The PBPK model of irbesartan developed in this study can be used to predict the pharmacokinetics of irbesartan and for individualized pharmacotherapy with irbesartan in individuals of various races, ages, and CYP2D6 genotypes.
Seok-Yong Lee, Chang-Keun Cho, Pureum Kang, Eunvin Ko and Chou Yen Mu Journal of Pharmacology and Experimental Therapeutics June 2023, 385 (S3) 173; DOI: https://doi.org/10.1124/jpet.122.508580
Abstract
Introduction: Irbesartan, a potent and selective angiotensin II type-1 receptor blocker, is mainly metabolized through oxidation and glucuronide conjugation. Its oxidation is primarily mediated by CYP2C9, and the genetic polymorphism of CYP2C9 significantly affects the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model of irbesartan in different CYP2C9 genotypes for individualized pharmacotherapy with irbesartan according to the genotype of CYP2C9.
Methods: The irbesartan PBPK model was established using PK-Sim® in three different CYP2C9 genotypes (CYP2C91/1, 1/3, and 1/13). Our pharmacogenomic data of irbesartan and a total of 15 clinical pharmacokinetic data of irbesartan with different demographic characteristics and dose regimens were leveraged to develop and validate the model. Physicochemical and ADME properties of irbesartan were obtained from previously reported data or optimized to capture the plasma concentration-time profiles in different CYP2C9 genotypes.
Results: Predicted plasma concentration-time profiles were visually similar to the observed profiles in different CYP2C9 genotypes. The ranges of fold errors for AUCinf and Cmax in development were 1.01-1.09 and 0.92-1.02 respectively, which were strictly satisfied with the evaluation criterion. The ranges of fold errors for AUCinf and Cmax in single-dose validation were 0.53-1.87 and 0.61-1.90, respectively, and in multiple-dose validation were 0.87-1.64 and 0.77-1.82, respectively, which were also within the evaluation criterion.
Conclusion: The PBPK model of irbesartan developed in this study can be used to predict the pharmacokinetics of irbesartan and for individualized pharmacotherapy with irbesartan in individuals of various races, ages, and CYP2D6 genotypes.