Farmacocinética Baseada em Fisiologia (PBPK) para predizer a farmacocinética dos enantiômeros de hidroxicloroquina de acordo com polimorfismos genéticos de CYP2D6 e CYP2C8
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2022-12-14
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Universidade Estadual Paulista (Unesp)
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Hidroxicloroquina (HCQ) é medicamento antimalárico utilizado para tratar infecções parasitárias por Plasmodium sp. O fármaco também é indicado para o tratamento de doenças inflamatórias e autoimunes, como infecções reumáticas e dermatológicas, artrite reumatoide, lúpus eritematoso sistêmico e discoide, e condições dermatológicas provocadas ou agravadas pela luz solar. A HCQ é um fármaco quiral disponível como mistura racêmica de R-HCQ e S-HCQ. Sua enantiosseletividade é descrita tanto na farmacocinética, como na farmacodinâmica e o medicamento final é disponível apenas na forma de racemato. A HCQ é metabolizada principalmente no fígado pelas enzimas CYP2D6, 3A4 e 2C8. Dados clínicos sugerem que variantes de CYP2D6 resultam em alteração no metabolismo de HCQ. Este estudo teve como objetivo desenvolver modelos farmacocinéticos baseados em fisiologia (PBPK) para predizer a disposição cinética dos enantiômeros de HCQ e avaliar o efeito de polimorfismos genéticos na exposição sistêmica de HCQ. A modelagem PBPK foi desenvolvida usando o simulador Simcyp V21. A construção do modelo foi baseada em parâmetros PK in vitro e em dados clínicos observados em voluntários adultos após a administração oral e intravenosa de HCQ. O modelo incorporou dados de cinética enzimática para as enzimas CYP2D6, CYP2C8 e CYP3A4, cujos valores de clearance intrínseco foram definidos por extrapolação retrógrada de forma a capturar a contribuição de cada isoforma na eliminação total de HCQ. As predições dos modelos PBPK finais foram verificadas em relação a dados PK observados em 3 estudos clínicos (administração intravenosa e oral) através dos perfis de concentração sanguínea e pela comparação dos parâmetros PK observados e preditos. O erro médio (MFE) é considerado satisfatório quando os parâmetros preditos encontram-se dentro de duas vezes o valor observado correspondente. Para a área sob a curva concentração sanguínea versus tempo (AUC) de R-HCQ e S-HCQ após administração IV, o MFE foi de 0,76 e 1. Para R-HCQ após administração oral, o MFE variou de 0,94-1 e 0,55-1,2 para os parâmetros AUC e concentração sanguínea máxima (Cmax). Para S-HCQ, os valores de MFE ficaram entre 0,71- 0,89 e 0,75-1,5 para AUC e Cmax, respectivamente. As razões R-HCQ/S-HCQ preditas/observadas para AUC (0,73-1,34) e Cmax (0,70-0,72) mostraram predizer a enantiosseletividade. Os modelos PBPK para os enantiômeros foram empregados para simular perfis de concentração sanguínea e parâmetros PK em fenótipos metabolizador normal (NM), lento (PM) e ultrarrápido (UM) de CYP2D6 e NM e PM de CYP2C8. As simulações mostraram que sujeitos PM para CYP2D6 apresentam aumento em média de 1,1 vezes na AUC, e sujeitos UM de CYP2D6 apresentaram redução de 0,9 vezes, em relação aos sujeitos NM de CYP2D6. Foram realizadas simulações de cenários clínicos improváveis de serem avaliados em estudos clínicos. Indivíduos com fenótipo PM para CYP2D6 e CYP2C8 em uso do inibidor de CYP3A4 claritromicina podem apresentar aumento médio na AUC de R-HCQ e S-HCQ de 2,34 e 2,68. Em conclusão, os modelos PBPK desenvolvidos se mostraram adequados para a predição da cinética enantiosseletiva de HCQ e podem ser aplicados para predizer interações complexas fármaco-fármaco-gene que não são facilmente avaliadas em estudos clínicos.
Hydroxychloroquine (HCQ) is an antimalarial drug used to treat Plasmodium sp. parasitic infections. The drug is also indicated for the treatment of inflammatory and autoimmune diseases, such as rheumatic and dermatologic infections, rheumatoid arthritis, systemic and discoid lupus erythematosus, and dermatologic conditions caused or aggravated by sunlight. HCQ is a chiral drug available as a racemic mixture of R-HCQ and S-HCQ. Its enantioselectivity is described in the pharmacokinetics and in the pharmacodynamics, and the final drug is available only as a racemate. HCQ is metabolized primarily in the liver by CYP2D6, 3A4 and 2C8 enzymes. Clinical data suggest that CYP2D6 variants result in altered HCQ metabolism. This study aimed to develop physiology-based pharmacokinetic (PBPK) models to predict the kinetic disposition of R- and SHCQ and to evaluate the effect of genetic polymorphisms in thesystemic exposure. PBPK modeling was developed using the Simcyp V21 simulator. Model development was based on in vitro PK parameters and clinical data observed in adult volunteers following oral and intravenous administration of HCQ. The model incorporated enzyme kinetics data for the enzymes CYP2D6, CYP2C8, and CYP3A4, whose intrinsic clearance values were defined by retrograde extrapolation to capture the contribution of each isoform to total HCQ elimination. Predictions of the final PBPK models were verified using observed PK data from 3 clinical studies (intravenous and oral administration) by comparing blood concentration profiles and observed and predicted PK parameters. The mean fold error (MFE) is considered satisfactory when all predicted parameters were within two fold the corresponding observed value. For the area under the blood concentration versus time curve (AUC) of R-HCQ and S-HCQ after IV administration, MFE was 0.76 and 1. For R-HCQ after oral administration, MFE values ranged from 0.94-1 and 0.55-1.2 for AUC and maximum blood concentration (Cmax). For S-HCQ, MFE values were 0.71-0.89 and 0.75-1.5 for AUC and Cmax, respectively. The predicted/observed R-HCQ/S-HCQ ratios for AUC (0.73-1.34) and Cmax (0.70-0.72) showed that our model was able to predict the enantioselectivity. PBPK models of R- and S-HCQ enantiomers were applied to simulate blood concentration profiles and PK parameters in normal metabolizer (NM), poor metabolizer (PM) and ultrarapid metabolizer (UM) phenotypes for CYP2D6 and NM and PM for CYP2C8. Simulations showed an average 1.1-fold increase in the AUC oin CYP2D6 PM, and a 0.9 fold reduction in CYP2D6 UM, relative to CYP2D6 NM subjects. Simulations showed that a 1.5-fold increase in the AUC in CYP2C8 PM relative to CYP2C8 NM phenotype. Simulations of clinical scenarios unlikely to be evaluated in clinical studies were performed. Individuals with the PM phenotype for both CYP2D6 and CYP2C8 using the CYP3A4 inhibitor clarithromycin showed an average increase in the AUC of RHCQ and S-HCQ of 2.34 and 2.68 fold. In conclusion, PBPK models proved to be suitable for the prediction of the enantioselective kinetics of HCQ. The PBPK models can be applied to predict complex drug-drug-gene interactions that are not easily evaluated in clinical trials.
Hydroxychloroquine (HCQ) is an antimalarial drug used to treat Plasmodium sp. parasitic infections. The drug is also indicated for the treatment of inflammatory and autoimmune diseases, such as rheumatic and dermatologic infections, rheumatoid arthritis, systemic and discoid lupus erythematosus, and dermatologic conditions caused or aggravated by sunlight. HCQ is a chiral drug available as a racemic mixture of R-HCQ and S-HCQ. Its enantioselectivity is described in the pharmacokinetics and in the pharmacodynamics, and the final drug is available only as a racemate. HCQ is metabolized primarily in the liver by CYP2D6, 3A4 and 2C8 enzymes. Clinical data suggest that CYP2D6 variants result in altered HCQ metabolism. This study aimed to develop physiology-based pharmacokinetic (PBPK) models to predict the kinetic disposition of R- and SHCQ and to evaluate the effect of genetic polymorphisms in thesystemic exposure. PBPK modeling was developed using the Simcyp V21 simulator. Model development was based on in vitro PK parameters and clinical data observed in adult volunteers following oral and intravenous administration of HCQ. The model incorporated enzyme kinetics data for the enzymes CYP2D6, CYP2C8, and CYP3A4, whose intrinsic clearance values were defined by retrograde extrapolation to capture the contribution of each isoform to total HCQ elimination. Predictions of the final PBPK models were verified using observed PK data from 3 clinical studies (intravenous and oral administration) by comparing blood concentration profiles and observed and predicted PK parameters. The mean fold error (MFE) is considered satisfactory when all predicted parameters were within two fold the corresponding observed value. For the area under the blood concentration versus time curve (AUC) of R-HCQ and S-HCQ after IV administration, MFE was 0.76 and 1. For R-HCQ after oral administration, MFE values ranged from 0.94-1 and 0.55-1.2 for AUC and maximum blood concentration (Cmax). For S-HCQ, MFE values were 0.71-0.89 and 0.75-1.5 for AUC and Cmax, respectively. The predicted/observed R-HCQ/S-HCQ ratios for AUC (0.73-1.34) and Cmax (0.70-0.72) showed that our model was able to predict the enantioselectivity. PBPK models of R- and S-HCQ enantiomers were applied to simulate blood concentration profiles and PK parameters in normal metabolizer (NM), poor metabolizer (PM) and ultrarapid metabolizer (UM) phenotypes for CYP2D6 and NM and PM for CYP2C8. Simulations showed an average 1.1-fold increase in the AUC oin CYP2D6 PM, and a 0.9 fold reduction in CYP2D6 UM, relative to CYP2D6 NM subjects. Simulations showed that a 1.5-fold increase in the AUC in CYP2C8 PM relative to CYP2C8 NM phenotype. Simulations of clinical scenarios unlikely to be evaluated in clinical studies were performed. Individuals with the PM phenotype for both CYP2D6 and CYP2C8 using the CYP3A4 inhibitor clarithromycin showed an average increase in the AUC of RHCQ and S-HCQ of 2.34 and 2.68 fold. In conclusion, PBPK models proved to be suitable for the prediction of the enantioselective kinetics of HCQ. The PBPK models can be applied to predict complex drug-drug-gene interactions that are not easily evaluated in clinical trials.
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Hidroxicloroquina, Enantiômeros, PBPK, Polimorfismos genéticos, Hydroxychloroquine, Enantiomers, Genetic polymorphisms