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  • Title: Prediction of the tacrolimus population pharmacokinetic parameters according to CYP3A5 genotype and clinical factors using NONMEM in adult kidney transplant recipients.
    Author: Han N, Yun HY, Hong JY, Kim IW, Ji E, Hong SH, Kim YS, Ha J, Shin WG, Oh JM.
    Journal: Eur J Clin Pharmacol; 2013 Jan; 69(1):53-63. PubMed ID: 22660440.
    Abstract:
    PURPOSE: Tacrolimus is a commonly used immunosuppressant in solid organ transplantation recipients, but it is characterized by a narrow therapeutic range and large inter-individual variability. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene encoding P-glycoprotein (ABCB1), on the PK parameters in adult Korean kidney transplant recipients. METHODS: Clinical data were collected retrospectively for 400 days after the initiation of a tacrolimus-based immunosuppression therapy. Data from 2,788 trough blood samples obtained from 80 subjects were used to perform a population PK analysis with a nonlinear mixed-effect model (NONMEM). RESULTS: The estimated population mean values of clearance (CL/F) and volume of distribution (V/F) were 22.9 L/h and 716 L, respectively, and the k(a) was fixed to 4.5 h⁻¹. The CYP3A5 genotype, hematocrit level, and post-operative days were identified as the main covariates that influence CL/F, and body weight was found to have a significant effect on V/F. Other covariates, including ABCB1 genotype, corticosteroid dosage, sex, and other clinical data, did not contribute to the pharmacokinetics of tacrolimus. CONCLUSIONS: This tacrolimus population PK model will be a valuable tool in developing rational guidelines and provides a basis for individualized therapy after kidney transplantation in clinical settings of Korea.
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