他克莫司在中国肾移植患者中的群体药动学研究

IMS: To quantitatively evaluate pharmacokinetic parameters and variations of tacrolimus between the intra- and inter-individuals and to guide the individualized tacrolimus administration based on the identified impact factors leading to variations of pharmacokinetics of tacrolimus in adult renal transplantation patients.METHODS: Collecting blood tacrolimus concentration data and clinical information of renal transplant patients with different CYP3A4*1G and CYP3A5*3 alleles; putting the above data into Excel 2003,building the database,then sorting the format NONMEM data file desired; basing on one compartment model of first order absorption and elimination, and using stepwise regression method to build full model, inspecting the effects of covariant on the model based on the retro-rejection method and building and validating the final model of tacrolimus in adult renal transplantation patients. RESULTS: 1. 167 blood tacrolimus concentrations and 908 clinical information in cases of renal transplantation patients of were collected. 2. The genotypes of 167 kidney transplant patients were: 76 (45.5%) CYP3A4*1/*1，81 (48.5%) CYP3A4*1/*1G, 72 (43.1%) CYP3A5*1/*3，83 (49.7%) CYP3A5*3/*3. 3. The body weight, post operation days (POD), urea nitrogen, uric acid, felodipine, CYP3A4 and CYP3A5 genotypes stepped into full model of tacrolimus based on more than 60 thousand data about population statistics, physiological and pathologic indexes, genetic factors, coadministrations and blood concentrations of tacrolimus.4. CYP3A4 and CYP3A5 genotypes and POD got into the final model based on the retro-rejection method.5. CYP3A5*3 and CYP3A4*1G genetic polymorphism, and POD were the important factors leading to the apparent clearance variances and apparent volume variances of tacrolimus, respectively. PopPK parameters of tacrolimus: CL/F was 32.4 L h-1, V/F was 1700 L. Absorption rate consitant Ka was fixed at 3.09 h-1 , individual differences of the CL/F and V/F were 25.9% and 66.7%, respectively.6 The final model of tacrolimus was valid, stable and representative by Bootstrap verifying.CONCLUTIONS:There is no difference between Chinese and Caucasian in CL/F of tacrolimus.We quantitatively evaluate the effect of CYP3A5*3 on the variations of pharmacokinetic parameters of tacrolimus, and find CYP3A4*1G is the important factor leading to the variations of pharmacokinetic parameters of tacrolimus for the first time. The trough concentrations of tacrolimus are higher in patients with CYP3A5*3/*3 and CYP3A4*1/*1 genotypes than that in patients with CYP3A5*1/*1, CYP3A4*1/*3, CYP3A4*1/*1G and CYP3A4*1G /*1G genotypes. POD is the important factors leading to the apparent volume variances of tacrolimus. The valid, stable and representative PopPK model of tacrolimus is established in Chinese adult renal transplantation recipients.