Effects ofCYP3A5genotypes,ABCB1 C3435TandG2677T/Apolymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients

Abstract

1. 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 Chinese adult liver transplant recipients. 2. Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs. 3. A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6 L/h and 225 L, respectively. The absorption rate constant (Ka) was fixed at 4.48 h(-1). The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F. 4. Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.

The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts

“…Our previous studies have demonstrated that hemoglobin, total bilirubin, and blood urea nitrogen after transplantation are significantly associated with the bioavailability of tacrolimus 14 . Clinical assessment of these liver transplant receipts revealed that the blood tacrolimus level was inversely related to the liver function evaluated by the blood levels of total bilirubin and creatinine (Fig.…”

“…It has been reported that CYP3A5 genotypes affect the pharmacogenetics of tacrolimus 19, 20 because different CYP3A5 genotypes exert different characteristics of the expression of CYP3A5 14, 21 . This evidence may contribute to the interindividual variability of the tacrolimus metabolism.…”

Population pharmacokinetics of tacrolimus in paediatric systemic lupus erythematosus based on real-world study

“…[6][7][8][9][10][11][12][13][14][15] However, tacrolimus has a narrow therapeutic window and displays considerable interindividual and intra-individual variabilities in its pharmacokinetics, with poor correlation between drug dosage and blood concentrations, making it difficult to define an optimal dose schedule. 18 Currently, different tacrolimus PPK models have been set up for various populations including renal transplant patients, [19][20][21][22][23][24] liver transplant patients, [25][26][27][28][29][30] haematopoietic stem cell transplant patients 31 and lung transplant patients. Moreover, the population analysis methodology differentiates between interindividual variability and residual unexplained variability.…”

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in Chinese liver transplant patients

“…MAP has the following advantages: patient characteristics can be incorporated into the model to improve the prediction of individualized AUC; the predictive performance can be improved with additional data; the sampling time can be chosen flexibly; and different PK parameters can be predicted simultaneously. Different TAC PPK models have been established in various populations including renal transplant patients, liver transplant patients, hematopoietic stem cell transplant patients and lung transplant patients . Some studies have tried to estimate TAC AUC using MAP.…”

“…Some studies have tried to estimate TAC AUC using MAP. Some other TAC PPK studies focused on Chinese liver transplant patients . However, they only used conventional TDM data for modelling and assaying the individualized PPK parameters assay rather through Bayesian estimation.…”