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Objective To explore the influencing factors of blood concentration of tacrolimus in pediatric living donor liver transplant recipients and provide rationales for individualized administration of tacrolimus .Methods Trough concentrations (C0 ) , doses of tacrolimus , recipient age , gender , body weight ,donor and recipient CYP3A5 genotypes ,hematocrit (HCT ) and liver/kidney function related indicators at 3 ,5 ,7 ,14 days ,1 month , 2 months and 3 months post living donor liver transplantation were collected from a total of 100 pediatric recipients .Taking ratio of concentration to dose (C0 /D) as a dependent variable ,the influencing factors of blood concentration of tacrolimus were analyzed by multivariate stepwise regression .Results The influencing factors of blood tacrolimus concentration at 3d post-transplantation were recipient CYP3A5 genotyp , donor CYP3A5 genotype and weight of recipients . The major influencing factors at 5d post-transplantation were recipient & donor CYP3A5 genotypes , recipient weight and HCT . The major relevant factors at 7d posttransplantation were CYP3A5 of recipients ,age and HCT .The influencing factors at 14 days were the same as those at 2 months ,i .e .CYP3A5 genotype and weight of recipients .At 1 month the major influencing factors were weight of recipients ,CYP3A5 of recipients and alkaline phosphatase (ALP) ; CYP3A5 genotype and weight of recipients at 3 months . Further study on CYP3A5 genotype of donors and recipients , the C0 /D ratio of CYP3A5 genotype non-expression group was significantly higher than that of expression group in recipients and C0 /D ratio of donor CYP3A5 genotype nonexpression group was significantly higher than that of expression group .Conclusions The influencing factors of concentration of tacrolimusvary at different timepoints after liver transplantation . Paying close attention to the changes of CYP3A5 genotype , weight of recipients and related biochemical indexes and considering various influencing factors facilitate individualized dosing for improving the prognosis of pediatric recipients .
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Objective To provide a reference for the individualized medication of tacrolimus in children after living related liver transplantation,according to the effect of CYP3A5 genotyping on the concentration/dose ratio of tacrolimus in children with living related liver transplantation.Methods Peripheral blood samples were collected from children with living related liver transplantation in the transplant center.The CYP3A5 genotype was determined by polymerase chain reaction (PCR)pyrosequencing.Related indicators such as tacrolimus dose and concentration in children with living related liver transplantation were collected within 3 months after operation.According to the donor/receptor genotype,the donor/receptor expression group,the donor/receptor single expression group,and the donor/receptor non-expression group were set up.Tacrolimus concentration/dose (C0/D) ratio was statistically analyzed at 5th day,7th day,14th day,28th day,2nd month and 3rd month after administration.Results Among the 76 patients,there were 21 patients (27.63％) in CYP3A5 donor/receptor non-expression group,27 patients (35.53％) in donor/receptor single expression group,and 28 patients (36.84％) in the donor/receptor expression group.The time to the target concentration range (C0＞8 ng/mL) in CYP3A5 donor/receptor expression group was longer than in donor/receptor single expression group and donor/receptor non-expression group.Except for the individual time points,there were significant differences between CYP3A5 donor/receptor expression group and donor/receptor non expression group,or between donor/receptor non-expression group and donor/receptor single expression group,or between donor/receptor expression group and donor/receptor single expression group at rest time points (P＜0.05 for all).Conclusion In the CYP3A5 donor/receptor gene expression group,the higher dose was needed to reach the target concentration range than the gene single expression group and the donor/receptor non-expression group.Except for individual time points,there were significant differences in C0/D at rest different time points.Regardless of whether the donor or recipient contained the CYP3A5* 1 allele,C0/D was lower than the non-expressed type of the gene.Considering the polymorphism of the donor/receptor CYP3A5 gene,it was worthful for children with living related liver transplantation to allow the drug concentration to reach the therapeutic window as soon as possible and reduce organ rejection and adverse reactions.
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Objective To investigate the relationship between CYP3A5 gene polymorphism and tacrolimus concentration/dose ratio in children living donor liver transplantation and the correlation with clinical efficacy,for the relatives living donor liver transplantation in children tacrolimus individualized medication providing reference indicators.Methods Peripheral blood samples were collected from children with relatives living donor liver transplantation in the center of liver transplantation,the genotype of CYP3A5 was determined by polymerase chain reaction (PCR)/pyrophosphate sequencing,The dosage of tacrolimus and blood concentration,liver and kidney function and other related indicators were measured within 3 months after operation According to genotypes,the children can be divided into gene expression group (CYP3A5 *1/*1 and CYP3A5 *1/*3) and non-expression group (CYP3A5*3/*3).The drug concentration (C0),tacrolimus dose / body weight (D/W) ratio,drug concentration/dose (C0/D) ratio of each genotype at 1 day,3 d,5 d,7 d,14 d,28 d,2 months and 3 months after administration and the genotype at the time point on liver and kidney function was carried out statistics.Results Among the 80 cases,36 cases (45.0％) were CYP3A5*3/*3,37 cases (46.2％) were CYP3A5*1/*3,7 cases (8.8％) were CYP3A5*1/*1.CYP3A5 gene expression group reached a therapeutic concentration range (C0 ＞ 8 μg/L) than the gene non-expression group takes longer time.There was no significant difference in CYP3A5 gene expression group between the non-expression group on the initial dose (P＞ 0.05);CYP3A5 gene expression group than the non-expression group,tacrolimus C0 within 1 month after operation were statistically significant.CYP3A5 gene expression group than the non-expression group,tacrolimus D/ W in addition to the first day after surgery,other time points were statistically significant (P＜0.05).CYP3A5 gene expression group than the non-expression group,C0/D at the above time points were statistically significant (P＜0.05);There were no significant differences in liver and kidney function between the two genotypes (P ＞ 0.05),but there was significant difference in the alkaline phosphatase.Conclusion CYP3A5 gene expression in children than non-expression group of children need higher doses to reach the therapeutic drug concentration;CYP3A5 gene polymorphism had significant effects on early tacrolimus C0,D/W and C0/D values;CYP3A5 gene polymorphism is instructive for the administration of tacrolimus in children with living donor liver transplantation,CYP3A5 gene type tests should be regular,improve efficacy and reduce the incidence of adverse reactions.
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Objective To analyze and compare the dosage,blood concentration and metabolic characteristics of Tacrolimus (Tac) for pediatric patients who underwent living related liver transplantation (LRLT) or donation after cardiac death liver transplantation (DDLT).Methods The clinical data of 75 liver transplantation pediatric patients from October 2012 to August 2015 were retrospectively analyzed.According to the different source of donors,the recipients were divided into two groups:LRLT group (40 cases) and DDLT group (35 cases).Results (1) Under the condition of same initial Tac dosage,the Tac dosage in LRLT group was less than in DDLT group during the first 28 days post-transplantation (P＞ 0.05).However,the Tac dosage in DDLT group was significantly higher than in LRLT group on the second and third months after sugery (P =0.000).(2) Correlation analysis revealed that graft-recipient body weight ratio (GRWR) was correlated with Tac dosage (mg·kg-1 ·d-1) on the 14th day postoperative (LRLT group:r=0.579,P＜0.05;DDLT group:r =0.583,P＜0.05) and Tac concentration/dosage ratio (LRLT group:r =-0.607,P＜0.05;DDLT group:r=-0.680,P＜0.05).Conclusion Tac has a satisfactory anti-rejection effect on liver transplantation pediatric patients while the metabolism varied with each individual.There is a positive correlation between the early Tac dosage and the GRWR in both groups.It is necessary to set individualized Tac administration regimen according to the metabolic characteristics and GRWR.
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Objective To assess the efficacy and safety of extended-release versus standardrelease in kidney transplant recipients.Methods We searched Pubmed,Embase,Medline and Cochrane library databases in English and researched published randomized controlled trials (RCTs)focused on extended-release versus standard-release tacrolimus in renal transplant recipients until March 2016.The risk of bias assessment for RCTs was evaluated using the Cochrane Collaboration's tool,and quality of RCTs was assessed by the modified JADAD scale.Meta-analysis was conducted by Review Manager 5.3 and Stata SE 12.0.Results A total of 12 RCTs were included,involving 3 532 adult kidney transplant recipients.There was no significant difference between the two treatment groups in the endpoints such as acute rejection rate (RR =0.93[0.78 1.11],P =0.40),graft survival (RR=1.04[0.79-1.37],P =0.76),patient survival (RR =1.03[0.67-1.57],P =0.90),patients withdrawn (RR =1.07[0.95-1.22],P =0.26),estimated glomemlar filtration rate (eGFR) (MD =-0.52[-1.95,0.92],P =0.48),creatinine clearance (Ccr) (MD =-0.94 [-1.39,3.28],P =0.43),infection (RR=0.98[0.90-1.06],P =0.57),and new-onset diabetes rate (RR =0.91[0.67-1.23],P =0.53).Meanwhile,subgroup analysis of different patient population (early after transplantation vs.late after transplantation) showed similar results in the protocol.Conclusion The extended-release tacrolimus has similar efficacy and safety to the standard-release in kidney transplantation.
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Objective To investigate the efficacy,safety,economy evaluation of CYP3A5 * 3 gene polymorphism in providing individualized administration for the use of tacrolimus (Tac) in renal transplantation recipients.Method Pyrophosphate sequencing method was used to determine the CYP3A5 * 3 genotype of renal transplant patients in the first day after surgery.Computer-generated random numbers were used to assign 60 patients into experiment group or control group.Both groups of patients were routinely given the initial dose of Tac (4.0 mg/day) in the first day after surgery.The patients in the experiment group were given different doses of Tac based on the different CYP3A5 * 3 genotypes at the third day after surgery [for AA,AG:0.12 mg/(kg day),and for GG:0.06 mg/(kg day)].The patients in the control group were given different dosages of Tac according to drug concentration.The patients were followed up for 12 months,and different parameters were compared between two groups.A decision tree model was populated with data from the study and used to economics evaluation.Result At day 5 after the transplantation,significantly more patients in the experiment group were within the Tac target C0 range [90％ (27/30)] as compared to the control group [46.67％ (14/30) (P＜0.05).At this time point,the median Tac C0was 5.08 [(2.5-8.7) μg/ L] in the experiment group vs.5.29 [(1.3-13.6) μg/L] in the control group (P＜0.05).When C0/ D was analyzed according to CYP3A5 * 3 genotype,we found the mean C0/D in the both groups with CY3A5 * 3/* 3 ＞CYP3A5 * 3/* 1 ＞ CYP3A5 * 1/* 1.It was noted that the time to achieve target Tas was (4.40 ± 0.97) in the experiment group,vs.(7.57 ± 3.42) in the control group.In total,the number of daily dose modifications was 11 in the experiment group and 49 in the control group in two weeks after transplantation (P＜0.05).Renal function at day 14 after transplantation and adverse events during 12 months of follow-up were similar in both groups.In total,10 adverse events were reported in the experiment group and 11 in the control group (P＞0.05).The results of costeffectiveness analysis showed that the cumulative costs and effects in the experiment group were ￥ 38 067 and 0.90 quality-adjusted life years gained,and those in the control group were ￥38 681 and 0.87 quality-adjusted life years gained,respectively.In the base case analyses,experiment group was more cost-effective.Conclusion Individualized adjustment of Tac doses for patients according to recipients different CYP3A5 * 3 genotypes is beneficial for reaching target concentration as soon as possible and more cost-effective.But the demonstration of the clinical relevance of this approach was not achieved.Higher methodological quality,and larger sample size study are still needed.
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Objective To evaluate the efficacy and safety of sirolimus and tacrolimus after renal transplantation.Method PubMed,Web of knowledge,Medline and the Cochrane controlled trials register,Chinese Biomedicaldatabase,and Vip database were searched with the terms and Boolean operators as (kidney transplantation OR renal transplantation) AND (sirolimus OR rapamycin OR rapamune) AND (tacrolimus OR FK506 OR prograf).Results retrieved were updated on November,2015.Data were extracted for patient and graft mortality,acute rejection (AR),wound complications,infection,GFR,withdrawl.Professional meta analysis software RevMan 5.3 was employed.Result Altogether,1810 patients from 10 randomized controlled trials (RCTs) were included.Patients in the sirolimus group showed a decreased rate of graft mortality and infection (RR =0.63,95％ CI,0.45-0.89,P=0.009;RR=4.42,95％ CI,1.73-11.31,P=0.002).Patients in the sirolimus group showed an increased rate of AR,wound complications,GFR,withdrawl (SMD=-0.52,95％ CI,-0.73-0.31,P＜0.000 01;RR=0.54,95％ CI,0.40-0.73,P＜0.000 1;RR=0.17,95％ CI,0.11-0.25,P＜0.000 01;RR =0.44,95％ CI,0.37-0.51,P＜0.000 01).The patient mortality was insignificantly different between two groups.Conclusion This meta-analysis concluded that sirolimus showed advantage over tacrolimus about safety when used early after renal transplantation.The options of immunosuppressive regimens after kidney transplantation should be based on the specific condition.To obtain more reliable and accurate clinical data,the RCTs with more rational design,higher methodological quality,larger sample size,including domestic patients,longer follow-up are still needed.