Population Pharmacokinetic Analysis Of Tacrolimus In Chinese Han Cardiac Transplant Recipients Based On Gene Polymorphism

PurposeThe study aims to analyze the correlation between genetic polymorphisms and blood concentration of tacrolimus in Han patients with heart transplantation,and build a population pharmacokinetic model on this basis.Methods1.According to the inclusion and exclusion criteria,the adult heart transplant patients who took tacrolimus were enrolled,and blood samples were collected.The blood drug concentration was determined by enzyme multiplied immunoassay technique.The 24 SNP-genotypes including drug metabolizing enzymes,drug transporters,regulatory factors,and target proteins were detected by the flight mass spectrometry system.The patients’demographic data,medication information,biochemical indicators,combined medication and combined disease data were collected to investigate the influence of various genetic and non genetic factors on the blood concentration of tacrolimus.2.By establishing an analysis plan,creating a data set,data exploratory analysis,building a basic and covariate model,and evaluating the model,the final population pharmacokinetic model of tacrolimus for Han heart transplant patients is established.Results1.The data of 53 heart transplant patients were included in the statistics.The genetic polymorphisms of CYP3A4*18B（rs2242480）and CYP3A5*3（rs776746）have an impact on the blood concentration of tacrolimus in Chinese Han heart transplant patients.While The genetic polymorphisms of CYP3A5（rs4646450）,ABCB1（rs1045642,rs2032582,rs1128503）,ABCB2（rs3740066）,C6（rs10052999,rs9200）,POR（rs1057868）,IL3（rs181781）,IL10（rs1800871,rs1800872,rs1800896）,IL18（rs1946518,rs5744247）,PXR（rs227607,rs3814055）,SUMO4（rs237025）,HSD11B1（rs4844880,rs846908,rs846910）and PPAR-α（rs4823613）have no significant effect.TLR4（rs1927907）did not comply with Hardy-Weinberg equilibrium analysis and was not included in the analysis.2.The 547 blood drug concentration data of 53 heart transplant patients were included in the analysis,the constructed population pharmacokinetic model of tacrolimus is a one compartment model with first order absorption and first order elimination.The estimated apparent clearance and apparent volume of distribution are532.5 L/h and 16.87 L,respectively.Ccr（Creatinine clearance）is the main covariate that affects the volume of distribution,and ALB（albumin）,POD（postoperative time）,rs2242480（CYP3A4*18B）gene polymorphisms are the main covariates that affect clearance.The population pharmacokinetic model of tacrolimus was constructed as V/F=532.499*（Ccr/77.03）^-0.828779*exp（n V）;CL=16.8733*（ALB/39.3）^-0.956541*（POD/26）^0.445981*（1+0.354619*（rs2242480=2））*（1+0.581502*（rs2242480=3））*exp（n CL）.rs2242480 genotype:CC is 1,TT is 2;CT is 3.The internal verification of goodness of fit plots and the bootstrap method indicate that the model is stable and the fit is good.Conclusion1.The genetic polymorphisms of CYP3A4*18B（rs2242480）and CYP3A5*3（rs776746）have an impact on the blood concentration of tacrolimus in Chinese Han heart transplant patients.2.The population pharmacokinetic model shows that in heart transplant patients,creatinine clearance affects the volume of distribution of tacrolimus,while serum albumin,postoperative time and CYP3A4*18B（rs2242480）gene polymorphisms affect the clearance rate of tacrolimus.