Population Pharmacokinetics Study Of Tacrolimus In Kindey Transplant Patients

Aim: Tacrolimus is the first-line drug used for immunosuppression of kidney transplants.Blood concentrations need to be examined because of the narrow differences in the therapeutic window and the large differences in pharmacokinetics/pharmacodynamics.To analyze the relationship between different genotypes and C0/D of tacrolimus in patients after transplantation.Non-linear mixed-effect kinetics model was used to investigate the covariates affecting the pharmacokinetic parameters of tacrolimus population through NONMEN software.Establishing a Population Pharmacokinetic Model Provides Reference for Clinical Individualization of Tacrolimus.Meterial & Methods: 1.The concentration of tacrolimus was determined by chemiluminescence immunoassay.According to the Guide to the Application of Tacrolimus in Clinical Kidney Transplantation in 2016,we analyze the distribution of blood concentration of patients during each time period.2.The MASSARRAY analysis was performed on 103 blood samples of renal transplant patients and the results were processed with SPSS19.0.To investigate the relationship between ABCB1,IL10,IL4 R,POR,CYP3A4,and CYP3A5 genotypes and C0/D at 7d,15 d,30d,60 d after renal transplantation.3.Collecting the tacrolimus blood drug trough concentrations at multiple time points about 141 kidney transplant patients,and we compiled basic information such as sex,age,weight,and liver and kidney function indicators,combined medications for each patient.Fluorescence analyzer was used to detect CYP3A4*18B and CYP3A5*3 genotypes in patients,and POR*28 polymorphism was detected by direct sequencing.Pharmacokinetics studies of tacrolimus were performed using the NONMEM method to estimate pharmacokinetic parameters and inter-and intra-individual variability in patients,and the final model was evaluated using Bootstrap method.And we collected another 15 patients informations for clinical verification.Results: 1.The plasma concentration distribution were analyzed about 103 renal transplant patients,including 70 males and 33 females,mean age(37.63±9.83),range(18-64 years),mean body weight(56.61±9.21)kg,range(35~80kg).After analysis,the concentration of renal transplant patients was collected the the normal range proportion is 60.1% within 1 month.With the adjustment of the dose and the extension of the transplantation time,the percentage of the normal concentration monitored also increases.2.Of the 103 patients tested,there were 8 cases(7.8%)in AA type,57 cases(55.3%)in AG type,38 cases(36.9%)in GG type about rs1045642;AA type in rs1128503 was 55 cases(54.5%),AG type 39 cases(38.6%),GG type 7 cases(6.9%);AA type in IL10 rs1800871 was 48 cases(46.6%),AG type 45 cases(43.8%),GG type 10 cases(9.7%);rs1800896 TT type 88 cases(84.6%),CT type 16 cases(15.4%);IL4R type AA 69 cases(67.0%),AG type 31 cases(30.1%),GG Type 3 cases(2.9%);POR AA type 40 cases(38.8%),AG type 45 cases(43.8%),GG type 18 cases(17.4%);CYP3A5 TT type 8 cases(7.8%),CT type 35 cases(34.0%),CC type 60 cases(58.2%);CYP3A4 AA type 85 cases(82.5%),AG type 11 cases(10.7%),GG type 7 cases(6.8%).The analysis showed that POR*28,CYP3A4,and CYP3A5 gene polymorphisms were associated with individual differences in pharmacokinetics of tacrolimus.The effects of multidrug resistance genes ABCB1,IL10,and IL4 R on tacrolimus C0/D were not statistically significant(p>0.05).3 There were 141 renal transplant recipients,including 96 males and 45 females.The average age was(38.26±9.95),the range was(18-64),the average weight was(57.02±9.92)kg,and the range was(36-80 kg)..The tacrolimus dose and human trough concentration were(3.12±0.99)(mg)and(12.62±4.15)(? mol/L).The frequencies of the CYP3A4*18B,CYP3A5*3,and POR*28 were 9.22%,76.24%,and 42.55%.In this part,141 patients were collected,including 96 males and 45 females.The final model is:CLi=27.72·(WT/70)0.75·(HCT /0.35)-0.501·(POD/180)0.0306·FCYP3A5·e? i/L·H-1.That is,the fixed effect parameters affecting the blood concentration of tacrolimus were selected: kidney transplant patient weight,postoperative time,hematocrit and CYP3A5 gene polymorphism,and patient demographics(age,gender,weight,etc.),liver and kidney function indicators,combined medications and CYP3A4*1G and POR*28 genotypes had no effect on CL/F.The model has been externally verified by the Bootstrap method.The model shows that the model has good stability and effectiveness.Conclusions: This study analyzed the distribution of blood concentration of postoperative tacrolimus in renal transplant recipients.We used the MASSARRAY method to detect the SNP genotypes of ABCB1,IL10,IL4 R,POR,CYP3A4,and CYP3A5.It was concluded that POR,CYP3A4,and CYP3A5 are the genes that have a greater influence on the plasma concentration of tacrolimus in patients.In this paper,for the first time,the distribution of CYP3A4*18B,CYP3A5*3 and POR*28 related genes in renal transplant patients from two hospitals in Nanchang was combined to establish a relevant PPK model and clinical validation.Calculate the dose required to reach the target concentration by the model,and provide a reference for clinically rational individualized administration.