Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms

Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms

Abstract 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...

Full description

Saved in:
Bibliographic Details
Main Authors: Gabriella de Souza Gomes Ribeiro, Leandro Francisco Pippa, Fernanda de Lima Moreira, Natália Valadares de Moraes
Format: Article
Language:English
Published: Universidade de São Paulo 2025-01-01
Series:Brazilian Journal of Pharmaceutical Sciences
Subjects:
Hydroxychloroquine
Enantiomers
PBPK
Gene polymorphisms
Drug interactions
Online Access:http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502025000100325&lng=en&tlng=en
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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.
ISSN:2175-9790

Similar Items