Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients
Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients
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DOI：
10.1111/bcp.12174
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发表时间：
2014-01-01
影响因子：
3.4
通讯作者：
McElnay, James C.
中科院分区：
文献类型：
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作者：
Jalil, Mariam H. Abdel;Hawwa, Ahmed F.;McElnay, James C.
目的建立一个群体药代动力学模型，描述他克莫司在肝移植后的表观清除量，以及可能导致儿童肝移植后患者间药代动力学变异的潜在人口统计学、临床和遗传控制因素。方法本研究回顾分析了43名儿童肝移植后一年内他克莫司的全血给药前浓度(n=628)。结果最终模型将移植后时间和细胞色素P3A5*1等位基因识别为影响他克莫司表观清除量的协变量：TVCL=12.9x(重量/13.2)(0.75)xEXP(-0.00158 x TPT)x EXP(0.428 x CYP3A5)，其中TVCL为表观清除量的典型值，TPT为移植后时间(以天数为单位)，CYP3A5为1，其中*1等位基因存在，否则为0。他克莫司表观清除量的总体估计值和个体间变异系数(%CV)分别为0.9771h(-1)kg(-1)(95%CI 0.958，0.996)和40.0%，而观察值和预测值的残差为35.4%。结论他克莫司表观清除量受移植后时间和细胞色素P3A5型的影响。这项研究的结果一旦得到大规模前瞻性研究的证实，就可以与治疗药物监测结合起来，建议调整他克莫司的剂量，不仅要考虑体重，还要考虑他克莫司清除量的遗传和时间相关变化。
AimsTo build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.MethodsThe present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates.ResultsThe final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equationTVCL = 12.9 x (Weight/13.2)(0.75) xEXP(-0.00158 x TPT) x EXP (0.428 x CYP3A5)where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977lh(-1)kg(-1) (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%.ConclusionTacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.