Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms
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https://doi.org/10.1590/Palavras-chave:
Hydroxychloroquine, Enantiomers, PBPK, Gene polymorphisms , Drug interactionsResumo
Hydroxychloroquine (HCQ) is a chiral drug used to treat malaria and inflammatory diseases, available as a racemic mixture of R-and S-HCQ. This work aimed to build physiologically-based pharmacokinetic (PBPK) models to predict the pharmacokinetics (PK) of R-and S-HCQ and assess the impact of major genetic polymorphisms on PK. Whole-body PBPK models accounting for first-order absorption, Rodgers and Rowland distribution method, and enzyme kinetics data were built for R-and S-HCQ. The models were verified by comparing predicted PK parameters with observed ones, with a mean error within the acceptable range (0.5-2 fold). Simulations covered CYP2D6 normal metabolizer (NM), poor metabolizer (PM), and ultra-rapid metabolizer (UM) phenotypes, as well as CYP2C8 NM and PM phenotypes. The results revealed a 1.1-fold increase in area under the curve blood concentration versus time (AUC) for CYP2D6 PM individuals and a 0.9-fold reduction for UM individuals compared to NM individuals. In addition, simulations with CYP2D6 and CYP2C8 PM phenotype individuals combined with the CYP3A4 inhibitor clarithromycin showed increased AUC for R-and S-HCQ of 2.34 and 2.68, respectively. These PBPK models offer reliable predictions for R-and S-HCQ enantioselective kinetics and shed light on previously unexplored scenarios.
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