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KMID : 0043320230460110939
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Archives of Pharmacal Research
2023 Volume.46 No. 11 p.939 ~ p.953
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Physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes
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Cho Chang-Keun
Kang Pu-Reum
Jang Choon-Gon
Lee Seok-Yong
Lee Yun-Jeong
Choi Chang-Ik
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Abstract
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Irbesartan, a potent and selective angiotensin II type-1 (AT 1 ) receptor blocker (ARB), is one of the representative medicationsfor 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 signifi cant alterations inthe pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) modelto predict the pharmacokinetics of irbesartan in diff erent CYP2C9 genotypes. The irbesartan PBPK model was establishedusing the PK-Sim ® software. Our previously reported pharmacogenomic data for irbesartan was leveraged in the developmentof 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 modelingsoftware, or optimized to fi t the observed plasma concentration?time profi les. Model evaluation was performed by comparingthe predicted plasma concentration?time profi les and pharmacokinetic parameters to the observed results. Predicted plasmaconcentration?time profi les were visually similar to observed profi les. Predicted AUC inf in CYP2C9*1/*3 and CYP2C9*1/*13genotypes were increased by 1.54- and 1.62-fold compared to CYP2C9*1/*1 genotype, respectively. All fold error valuesfor AUC and C max in non-genotyped and CYP2C9 genotyped models were within the two-fold error criterion. We properlyestablished the PBPK model of irbesartan in diff erent CYP2C9 genotypes. It can be used to predict the pharmacokinetics ofirbesartan for personalized pharmacotherapy in individuals of various races, ages, and CYP2C9 genotypes.
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KEYWORD
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Antihypertensive pharmacotherapy, CYP2C9, Physiologically based pharmacokinetic (PBPK) model, Irbesartan, Genetic polymorphism
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