Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes

Abstract

Metoprolol, a selective beta(1)-adrenoreceptor blocking agent used in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes alpha-hydroxylation and O-desmethylation. As CYP2D6 is genetically highly polymorphic and the enzymatic activity differs greatly depending on the presence of the mutant allele(s), the pharmacokinetic profile of metoprolol is highly variable depending on the genotype of CYP2D6. The aim of study was to develop the physiologically based pharmacokinetic (PBPK) model of metoprolol related to CYP2D6 genetic polymorphism for personalized therapy with metoprolol. For PBPK modelling, our previous pharmacogenomic data were used. To obtain kinetic parameters (K-m, V-max, and CLint) of each genotype, the recombinant CYP enzyme of each genotype was incubated with metoprolol and metabolic rates were assayed. Based on these data, the PBPK model of metoprolol was developed and validated in different CYP2D6 genotypes using PK-Sim (R) software. As a result, the input values for various parameters for the PBPK model were presented and the PBPK model successfully described the pharmacokinetics of metoprolol in each genotype group. The simulated values were within the acceptance criterion (99.998% confidence intervals) compared with observed values. The PBPK model developed in this study can be used for personalized pharmacotherapy with metoprolol in individuals of various races, ages, and CYP2D6 genotypes.