PURPOSE: To establish the population pharmacokinetic (PPK) model of cyclosporine (CsA) in Chinese renal transplant recipients and evaluate the influence of various indexes including CYP3A5 and MDR1 genetic polymorphism on pharmacokinetic parameters. METHODS: Trough (C(0)) and peak (C(2)) CsA concentration were monitored conventionally after renal transplantation. C(0) and C(2) were collected for 5 months in 146 patients. The CYP3A5*3 genotype and MDR1 haplotype were determined by methods based on amplification refractory mutant PCR. The data were analyzed by nonlinear mixed-effect modeling (NONMEM). The model was evaluated using goodness of fit plots and relative error measurements. Physiological and pathological factors including CYP3A5 and MDR1 genotypes were evaluated as covariates of CsA pharmacokinetic parameters. RESULTS: Pharmacokinetics of CsA was best described by a one-compartment disposition model followed a first-order absorption process. The estimated clearance (CL/F) was 49.5 l·h(-1), the volume of distribution (Vd/F) was 226 l. K(a) was fixed as 1.25 h(-1). Post-transplant data, body weight, total bilirubin, and MDR1 genotype were covariates of CL/F (P < 0.005). Gender and MDR1 haplotype were covariates of Vd/F (P < 0.005). The AUC estimated based on the Bayesian method was 7,465 ± 1,708 ng·h·ml(-1) (2,946 ∼13,926 ng·h·ml(-1)). CONCLUSION: The PPK model developed in this study could be used to optimize CsA dose for Chinese renal transplant recipients by using conventional therapeutic drug monitoring (TDM) data.
PURPOSE: To establish the population pharmacokinetic (PPK) model of cyclosporine (CsA) in Chinese renal transplant recipients and evaluate the influence of various indexes including CYP3A5 and MDR1 genetic polymorphism on pharmacokinetic parameters. METHODS: Trough (C(0)) and peak (C(2)) CsA concentration were monitored conventionally after renal transplantation. C(0) and C(2) were collected for 5 months in 146 patients. The CYP3A5*3 genotype and MDR1 haplotype were determined by methods based on amplification refractory mutant PCR. The data were analyzed by nonlinear mixed-effect modeling (NONMEM). The model was evaluated using goodness of fit plots and relative error measurements. Physiological and pathological factors including CYP3A5 and MDR1 genotypes were evaluated as covariates of CsA pharmacokinetic parameters. RESULTS: Pharmacokinetics of CsA was best described by a one-compartment disposition model followed a first-order absorption process. The estimated clearance (CL/F) was 49.5 l·h(-1), the volume of distribution (Vd/F) was 226 l. K(a) was fixed as 1.25 h(-1). Post-transplant data, body weight, total bilirubin, and MDR1 genotype were covariates of CL/F (P < 0.005). Gender and MDR1 haplotype were covariates of Vd/F (P < 0.005). The AUC estimated based on the Bayesian method was 7,465 ± 1,708 ng·h·ml(-1) (2,946 ∼13,926 ng·h·ml(-1)). CONCLUSION: The PPK model developed in this study could be used to optimize CsA dose for Chinese renal transplant recipients by using conventional therapeutic drug monitoring (TDM) data.
Authors: E Hustert; M Haberl; O Burk; R Wolbold; Y Q He; K Klein; A C Nuessler; P Neuhaus; J Klattig; R Eiselt; I Koch; A Zibat; J Brockmöller; J R Halpert; U M Zanger; L Wojnowski Journal: Pharmacogenetics Date: 2001-12
Authors: K S Lown; J C Kolars; K E Thummel; J L Barnett; K L Kunze; S A Wrighton; P B Watkins Journal: Drug Metab Dispos Date: 1994 Nov-Dec Impact factor: 3.922