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...
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Universidade de São Paulo
2025-01-01
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| Series: | Brazilian Journal of Pharmaceutical Sciences |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502025000100325&lng=en&tlng=en |
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| author | Gabriella de Souza Gomes Ribeiro Leandro Francisco Pippa Fernanda de Lima Moreira Natália Valadares de Moraes |
| author_facet | Gabriella de Souza Gomes Ribeiro Leandro Francisco Pippa Fernanda de Lima Moreira Natália Valadares de Moraes |
| author_sort | Gabriella de Souza Gomes Ribeiro |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9aa2931a5672498284c8d04903070028 |
| institution | Kabale University |
| issn | 2175-9790 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Universidade de São Paulo |
| record_format | Article |
| series | Brazilian Journal of Pharmaceutical Sciences |
| spelling | doaj-art-9aa2931a5672498284c8d049030700282025-01-21T07:41:48ZengUniversidade de São PauloBrazilian Journal of Pharmaceutical Sciences2175-97902025-01-016110.1590/s2175-97902025e24302Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphismsGabriella de Souza Gomes RibeiroLeandro Francisco PippaFernanda de Lima MoreiraNatália Valadares de Moraeshttps://orcid.org/0000-0002-4389-058XAbstract 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502025000100325&lng=en&tlng=enHydroxychloroquineEnantiomersPBPKGene polymorphismsDrug interactions |
| spellingShingle | Gabriella de Souza Gomes Ribeiro Leandro Francisco Pippa Fernanda de Lima Moreira Natália Valadares de Moraes Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms Brazilian Journal of Pharmaceutical Sciences Hydroxychloroquine Enantiomers PBPK Gene polymorphisms Drug interactions |
| title | Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| title_full | Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| title_fullStr | Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| title_full_unstemmed | Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| title_short | Physiologically-based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| title_sort | physiologically based pharmacokinetic modeling of enantioselective hydroxychloroquine kinetics and impact of genetic polymorphisms |
| topic | Hydroxychloroquine Enantiomers PBPK Gene polymorphisms Drug interactions |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502025000100325&lng=en&tlng=en |
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