RESUMO
PURPOSE: High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination. METHODS: A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients). RESULTS: A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing. CONCLUSIONS: The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.
Assuntos
Técnicas de Genotipagem/métodos , Linfoma não Hodgkin , Taxa de Depuração Metabólica/genética , Metotrexato/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antimetabólitos Antineoplásicos/farmacocinética , Teorema de Bayes , Superfície Corporal , China/epidemiologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodosRESUMO
AIM: To investigate the association between donor CYP3A5 and ABCB1 polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients. METHODS: The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors. RESULTS: There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor-recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis. CONCLUSION: A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes.
Assuntos
Citocromo P-450 CYP3A/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/genética , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Tacrolimo/uso terapêutico , Adulto JovemRESUMO
AIM: To investigate the impact of polymorphisms in the FPGS, GGH and SLCO1B1 genes on high dose methotrexate (HD-MTX) related toxicity in Chinese patients with non-Hodgkin lymphoma (NHL). MATERIALS & METHODS: We analyzed FPGS (rs10106), GGH (rs719235, rs10464903, rs12681874), SLCO1B1 (rs4149056) genetic polymorphisms in 105 Chinese patients with NHL treated with HD-MTX. RESULTS: There was a statistically significant impact of the SLCO1B1 rs4149056 polymorphism on hepatotoxicity. Patients with TC and CC genotype had more hepatotoxicity than TT genotype (60 vs 32.94%, p = 0.025). After adjusting for disease stage, dosage, infusion time and therapy method, SLCO1B1 rs4149056 genotype remained significantly associated with hepatotoxicity (p = 0.028). CONCLUSION: SLCO1B1 rs4149056 genetic variants can affect the HD-MTX-related toxicity in Chinese patients with NHL.
