A carregar...
Publicação
" Impacto da farmacogenética na farmacocinética dos antirretrovíricos em doentes coinfetados por vírus da imunodeficiência humana (VIH) e vírus da hepatite B (VHB) e/ou Vírus da hepatite C (VHC)"
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 5.69 MB | Adobe PDF |
Resumo(s)
Vários fatores originam heterogeneidade da resposta à terapêutica ARV. A ocorrência de polimorfismos genéticos, nomeadamente em enzimas de conjugação, isoenzimas do citocromo P450 e proteínas transportadoras MDR, MRP e SLC, podem ser causa de variabilidade farmacocinética de alguns ARV, podendo originar falência vírica ou toxicidade medicamentosa. A coinfeção por VHB e/ou VHC, pode constituir um fator condicionador da disposição dos ARV no organismo. Avaliou-se o impacto de polimorfismos genéticos das proteínas metabolizadoras e transportadoras de fármacos, na variabilidade farmacocinética de EFV, NVP, ATV, LPV, e analisou-se o impacto da coinfeção por VHB e/ou VHC na referida variabilidade. Foram avaliados 21 polimorfismos nos genes CYP2A6, CYP2B6, CYP3A5, UGT2B7, ABCB1, ABCC4, ABCC10, SLCO1B1, SLC3A1, NR1\2 e NR1\3. Foram efetuadas as correlações com o tempo de semivida e concentrações plasmáticas dos fármacos. Para o EFV, foi desenvolvido um modelo farmacocinético populacional através de modelação de efeitos mistos não lineares, onde se determinaram os parâmetros farmacocinéticos populacionais (Ka=1,39h-1 CV=0; Vd/F = 293L CV=43%; Cl/F=19,6L/h, CV=49%; t1/2= 10,4h). Na avaliação farmacogenética, foram os polimorfismos dos genes codificadores para as enzimas metabolizadoras do EFV, nomeadamente ao nível do gene CYP2B6, que mais contribuíram para a variabilidade farmacocinética dos ARV analisados. O modelo farmacocinético demonstrou que os polimorfismos associados ao haplótipo CYP2B6*6 (inclui 516G>T e 785A>G), são os que têm maior influência na preditibilidade dos parâmetros farmacocinéticos do EFV. Através do software PKS®, utilizando os parâmetros farmacocinéticos populacionais e ajustando para o polimorfismo CYP2B6*6, efetuaram-se simulações posológicas em 10 doentes medicados com EFV, que se encontravam acima da margem terapêutica. Observou-se a possibilidade de diminuir a dose do EFV para 400mg/dia em 70% dos doentes e para 200mg/dia em 30%, assegurando as concentrações plasmáticas nas margens terapêuticas. De forma a otimizar a relação custo/oportunidade, considerou-se a possibilidade de usar o valor de GGT (parâmetro bioquímico mais fortemente associado a concentrações plasmáticas elevadas de EFV) como critério de préseleção para realizar o referido teste. Os valores cut-off de GGT = 45,5 UI/L ou 54 UI/L, têm valor preditivo negativo e valor preditivo positivo de 1 e 0,24, 0,98 e 0,26, respetivamente. A utilização destes cut-offs, para seleção dos indivíduos para genotipagem, pode ser uma estratégia para gerir a ocorrência de toxicidade, em indivíduos em terapêutica com EFV.
Several factors cause heterogeneity of response to antiretroviral therapy. Genetic polymorphisms, particularly in conjunction enzyme, cytochrome P450 isoenzymes and transport proteins MDR, MRP and SLC, may cause pharmacokinetic variability in some ARVs, leading to viral failure or drug toxicity. The co-infection with HBV and/or HCV may change the ARV disposition in the organism. We evaluated the impact of genetic polymorphisms of drug metabolizing proteins and drug carriers in pharmacokinetic variability of EFV, NVP, ATV, and LPV. The impact of HBV and/or HCV co-infection in that variability was also analysed. 21 polymorphisms in CYP2A6, CYP2B6, CYP3A5, UGT2B7, ABCB1, ABCC4, ABCC10, SLCO1B1, SLC3A1, NR1\2 and NR 1\3 genes were evaluated. Correlations with the half-life and plasma concentrations of drugs were made. For EFV, it was developed a PK model using population pharmacokinetic modeling non-linear mixed effects, and was calculated the population PK parameters (Ka = 1,39h-1 CV = 0, Vd / F = 293L CV = 43%, Cl/F = 19,6L/h, CV = 49%, t1/2 = 10,4h). It was observed that polymorphisms of genes coding for metabolizing enzymes in the EFV, particularly in CYP2B6, contributed most to the PK variability of the ARV. The pharmacokinetic model showed that the polymorphisms in CYP2B6*6 haplotype (includes 516G>T and 785A>G) are the ones who have the greatest influence on the predictability of EFV PK parameters. By PKSTM software using population pharmacokinetic parameters and adjusting for the polymorphism CYP2B6*6, were carried out dose simulations in 10 patients taking EFV, which plasma concentrations were above the therapeutic range. There was the possibility of decrease the dose to EFV 400mg/day in 70% of patients and to 200 mg/day in 30%, ensuring the plasma concentrations at therapeutic margins. In order to optimize the cost/oportunity, it was considered the possibility of using GGT (clinical chemistry parameter strongly associated with elevated plasma concentrations of EFV), as pre-selection criterion for performing CYP2B6*6 pharmacogenetic test. The cut-off values of GGT = 45.5 IU/L or 54 IU/L, have negative predictive and positive predictive values of 1 and 0.24, 0.98 and 0.26, respectively. Using these cut-offs for selecting individuals for genotyping, can be a strategy to manage the occurrence of toxicity for subjects in EFV therapy.
Several factors cause heterogeneity of response to antiretroviral therapy. Genetic polymorphisms, particularly in conjunction enzyme, cytochrome P450 isoenzymes and transport proteins MDR, MRP and SLC, may cause pharmacokinetic variability in some ARVs, leading to viral failure or drug toxicity. The co-infection with HBV and/or HCV may change the ARV disposition in the organism. We evaluated the impact of genetic polymorphisms of drug metabolizing proteins and drug carriers in pharmacokinetic variability of EFV, NVP, ATV, and LPV. The impact of HBV and/or HCV co-infection in that variability was also analysed. 21 polymorphisms in CYP2A6, CYP2B6, CYP3A5, UGT2B7, ABCB1, ABCC4, ABCC10, SLCO1B1, SLC3A1, NR1\2 and NR 1\3 genes were evaluated. Correlations with the half-life and plasma concentrations of drugs were made. For EFV, it was developed a PK model using population pharmacokinetic modeling non-linear mixed effects, and was calculated the population PK parameters (Ka = 1,39h-1 CV = 0, Vd / F = 293L CV = 43%, Cl/F = 19,6L/h, CV = 49%, t1/2 = 10,4h). It was observed that polymorphisms of genes coding for metabolizing enzymes in the EFV, particularly in CYP2B6, contributed most to the PK variability of the ARV. The pharmacokinetic model showed that the polymorphisms in CYP2B6*6 haplotype (includes 516G>T and 785A>G) are the ones who have the greatest influence on the predictability of EFV PK parameters. By PKSTM software using population pharmacokinetic parameters and adjusting for the polymorphism CYP2B6*6, were carried out dose simulations in 10 patients taking EFV, which plasma concentrations were above the therapeutic range. There was the possibility of decrease the dose to EFV 400mg/day in 70% of patients and to 200 mg/day in 30%, ensuring the plasma concentrations at therapeutic margins. In order to optimize the cost/oportunity, it was considered the possibility of using GGT (clinical chemistry parameter strongly associated with elevated plasma concentrations of EFV), as pre-selection criterion for performing CYP2B6*6 pharmacogenetic test. The cut-off values of GGT = 45.5 IU/L or 54 IU/L, have negative predictive and positive predictive values of 1 and 0.24, 0.98 and 0.26, respectively. Using these cut-offs for selecting individuals for genotyping, can be a strategy to manage the occurrence of toxicity for subjects in EFV therapy.
Descrição
Tese de doutoramento, Farmácia (Biofarmácia e Farmacocinética), Universidade de Lisboa, Faculdade de Farmácia, 2015
Palavras-chave
Teses de doutoramento - 2015