Population Pharmacokinetics Of Tacrolimus In The Early Stage Post LDLT In Infant Biliary Atresia Recipients Based On CYP3A5 SNPs

Objective:To investigate the pharmacokinetic characteristics of tacrolimus?Tac?in the recipients with Biliary atresia?BA?in the first 3 months post living donor liver transplantation?LDLT?,and to analyze the influencing factors of the blood concentration of Tac.To establish a population pharmacokinetic?PPK?model of Tac in the LDLT recipients of biliary atresia infants,and to explore the relationship between the pharmacokinetic parameters and pathophysiological characteristics of Tac.The established model is externally validated and the blood concentration of Tac is predicted in combination with Bayesian method,in order to provide reference for optimizing individualized administration of Tac in this population.Methods:1.Influencing factors of Tac blood concentration in LDLT recipients with BA:Selection of research subjects according to inclusion exclusion criteria.The donor CYP3A5*3 genotypes?DCYP?and recipient CYP3A5*3?RCYP?genotypes were detected by Sanger sequencing.And the trough blood concentration?C₀?of Tac were detected by chemiluminescent microparticle immunoassay?CMIA?.Demographic information,graft to recipient weight ratio?GRWR?,daily dose?DD?and C₀ of Tac,liver and kidney function indicators of recipients were regularly recorded at 3rd,5th,7th,and 14th day,1 month,2 months,and 3 months post LDLT.Using C₀/D as the dependent variable,demographic characteristics,GRWR,liver and kidney function indicators,DCYP and RCYP were used as independent variables for multivariate stepwise regression analysis to explore the effects factors of Tac concentration.And the effect on the pharmacokinetics of Tac by CYP3A5*3 was further discussed according to the genotyping of the donor and the recipients.2.Population pharmacokinetic study of Tac in LDLT recipients of biliary atresia infants:PPK model of Tac in infant recipients within 3 months post LDLT was established by NONMEM.To investigate the covariance of age,sex,body weight,GRWR,postoperative time,DD,DCYP and RCYP,liver and kidney function of the recipients.And analysis the relationship between pharmacokinetic parameters of Tac and pathophysiological characteristics.Through the goodness of fit plots,2000-time Bootstrap?Bootstrap?and normal predictive distribution error?NPDE?,the accuracy of parameter estimation and the stability is evaluated.3.External validation and predictive ability evaluation of the PPK model:To investigate the external fitting of the model,the model was externally validated by another 10 recipients'data.Combined with Bayesian method,20 patients were predicted to predict the concentration of Tac at 3d,7d,14d,30d,60d and 90d after operation,and the predictive ability of the model was verified.Results:1.A total of 100 recipients were included in the study.The highest proportion of Tac blood concentration reached the target range in the first 3 months post LDLT was58.54%.DCYP,RCYP,GRWR,HCT,body weight and ALP were the main factors influencing the blood concentration of Tac.The frequency of the CYP3A5*1 genes of the donor and the recipients was 30.5%and 34.5%,respectively.The C₀/D of Tac in NEX-R/NEX-D group was significantly higher than that in EX-R/EX-D group in the first 2 months post LDLT?P<0.01?.And the C₀/D of the RCYP expresser was significantly lower than that in the non-expressor?P<0.01?.The donors expresser was significantly different from the non-expressor in the first 7days post LDLT?P<0.01?.2.The PPK model of Tac in infants with BA post LDLT was established with 60recipients.The final model showed the typical values of the apparent total clearance?CL/F?and apparent volume of distribution?V/F?of Tac were 5.37L·h^?1 and 84.1L,respectively.The DD,total protein,GRWR,hematocrit,postoperative time,DCYP and RCYP affect the CL/F of Tac.Moreover,the RCYP non-expressor showed a13.5%decrease in CL/F of Tac compared with the expression,and the DCYP non-expressor CL/F decreased by 10.5%compared with the expresser.The goodness of fit of the model was well;the successful rate of Bootstrap was 96.4%;the results of NPDE indicate that the model was fine.3.The model fits the external data to a good degree.The model has relatively unstable prediction of 3d and 14d after operation,and the prediction accuracy of 7d,30d,60d and 90d after operation was higher.And above 80%of the prediction error was within±30%at 30d,60d,and 90d post LDLT.The average prediction error reflected in the concentration of Tac was 0.99?0.02-3.04?ng·mL^?1Conclusions:1.Within 3 months post LDLT in infants with biliary atresia,the blood concentration fluctuation of the recipients was large,which was difficult to stabilize in the target range,and the maximum compliance rate was only 58.54%.The DCYP and RCYP,GRWR,hematocrit,body weight and ALP are the main factors affecting the concentration of tacrolimus,and these factors need to be considered for individualized administration in clinic.2.Both the donor and the recipients CYP3A5 genotype had a significant effect on the pharmacokinetics of Tac post LDLT in infant recipients.Among the 100recipients who were included in the study,the incidence of CYP3A5*1 alleles was34.5%,and 65.5%for the CYP3A5*3 allele.In order to predict the pharmacokinetics of tacrolimus,develop a reasonable dosing regimen and reduce the risk of acute rejection,it is particularly necessary to assess the donor and recipient CYP3A5genotypes pretransplantation.Clinicians should consider the DCYP and RCYP comprehensively to develop a reasonable treatment plan.3.A PPK model of Tac in infants with BA was established in the first 3 months post LDLT.The typical values of the CL/F and V/F of Tac were 5.37L·h^?1 and 84.1L.The goodness-of-fit plots were well,the success rate of 2000-time Bootstrap is 96.4%,and NPDE results of the model show that the model was well.4.DD,total protein,GRWR,hematocrit,postoperative time,DCYP and RCYP significantly affected the CL/F of Tac in infants LDLT recipients.Furthermore,compared with the expressers,the RCYP and DCYP non-expressers decreased the CL/F of Tac by 13.5%and 10.5%,respectively.5.The model has well fitting degree to external data and the higher predictive accuracy of 7d,30d,60d and 90d PLT.More than 80%of the prediction error are within±30%at 1-3 months PLT of the model which has reference value for the clinical development individualized immunosuppressive regimen.