Effect Of Diltiazem On The Pharmacokinetics Of Tacrolimus In Renal Transplant Patients:a Population Pharmacokinetics Analysis

Objectives:(1)To study the effect of CYP3A4、CYP3A5and MDR1gene polymorphism on the pharmacokinetics of diltiazem and tacrolimus in renal transplant patients.(2) To develop a population pharmacokinetics model of tacrolimus in renal transplant patients and evaluate the effect of diltiazem on the pharmacokinetics of tacrolimus, which provide the scientific basis for the individualized tacrolimus therapy in renal transplant patients.Methods:(1) The hospital records of renal transplant patients in the Third Xiangya Hospital of Center South Center were checked, and tacrolimus Concentration/Dose(C/D) was compared among amlodipine plus diltiazem group, felodipine plus diltiazem and control group (diltiazem alone) in the7,10,14days after transplantation accoding to the type of antihypertensive drugs.(2) The post transplant renal outpatients in the Third Xiangya Hospital of Center South Center,with steady-state concentration of tacrolimu and diltiazem, were selected. Classifying the patients into three groups according to the gene polymorphism of CYP3A4*1G、CYP3A5*3and MDR13435CT, and analyzing the effect of CYP3A4*1G,CYP3A5*3and MDR13435CT gene polymerphism on tacrolimus and diltiazem C/D by one-factor analysis of variance analysis.(3) The renal patients who were given tacrolimus after transplantation were selected from the Third Xiangya Hospital of Center South Center, and the tacrolims concentration following0,0.5,1,2,8,12h of morning medication were determined after3days tacrolimus administration. The patients who were given any calcium channel blockers have been excluded. Diltiazem should has been given when the tacrolimus concentration did not reach the target. The concentration of tacrolimus following0,0.5,1,2,8,12h of morning medication were determined after at least3days of continous diltiazem administration. The gene polymorphism of CYP3A4*1G、CYP3A5*3、 MDR1G2677T and C3435T were detected. Meanwhile, the demography, biochemical indicator, incorporated medicine, complication and tacrolimus trough concentration data of patients were collected. Nonlinear mixed-effects modelling was used to evaluate the data using NONMEM, and developing a population pharmacokinetics model for diltiazem-tacrolimus interaction.Results:1. In post transplant arterial hypertensive patients, compared to the tacrolimus C/D in7days after transplantation, both diltiazem and felodipine plus diltiazem significantly increased the tacrolimus C/D by47.7%(P=0.000) and39.9%(P=0.018), respectively.2. The tacrolimus C/D in felodipine plus diltiazem group was significantly lower than the value in control group in the7and14days after transplantation(P<0.05).3. The tacrolimus C/D in CYP3A4*1*1carriers was significantly higher than the CYP3A4*1G carriers(P=0.016), and tacrolimus C/D in CYP3A5*3*3carriers was significantly higher than the CYP3A5*1carriers(P=0.035).4. The diltiazem C/D in CYP3A4*1*1carriers was significantly higher than the CYP3A4*1G carriers (P=0.035), and there were no significant difference of diltiazem C/D between CYP3A5*3*3carriers and CYP3A5*1carriers in renal transplant patients.5. There was no significant difference of tacrolimus and diltiazem C/D among different MDR13435CT genotypes in renal transplant patients.6. A two-compartment pharmacokinetics model with first-order absorption and elimination adequately discribed the data. Tacrolimus typical clearance (CL/F), was18.2L/h. In the final model, diltiazem, genotype of CYP3A4*1G, prednisone and hematocrit showed significant influence on tacrolimus CL/F.Conclusions:1. Combination diltiazem with felodipine significantly increased tacrolimus C/D in post transplant arterial hypertensive patients, and the effect was less than the ones when diltiazem alone.2. The tacrolimus C/D was significantly associated with CYP3A4*1G and CYP3A5*3gene polymorphism.3. CYP3A4*1G gene polymorphism had significant influence on tacrolimus C/D, however, the correation between CYP3A5*3gene polymorphism and diltiazem was not found.4. MDR13435CT gene polymorphism did not have influence the C/D of tacrolimus and diltiazem in renal transplant patients.5. Population pharmacokinetics model of effect of diltiazem on tacrolimus pharmacokinetics in renal transplant patients was developed and validated. It was quantitatively evaluated the effects of CYP3A4*1G, prednisone, hematocrit on the pharmacokinetics of tacrolimus in renal transplant patients coadministered with diltiazem for the first time. The model was proved to be stable and effective, which can provides the scientific basis for individualized tacrolimus therapy.