肾移植受者联合用药和基因多态性对他克莫司群体药代动力学影响的研究

Effect of co-medications and genetic polymorphisms on the population pharmacokinetics of tacrolimus in kidney transplant recipients

目的通过群体药代动力学模型考察联合用药和基因多态性对他克莫司(TAC)代谢的影响,为肾移植受者TAC个体化治疗提供依据。方法收集162例成年肾移植受者1634个TAC稳态谷浓度血样。用非线性混合效应模型(NONMEM)建立群体药代动力学模型,通过拟合优度图(GOF图),正态化预测分布误差(NPDE)和自举法(Bootstrap)进行内部验证;另收集56例患者的602个谷浓度数据进行外部验证,以均方根误差(RMSE)、平均预测误差(MPE)和标准预测误差(SPE)评价模型的准确度和精密度。结果本研究在肾移植受者中建立了TAC的一级吸收和消除的一房室药代动力学模型。最终模型的表观清除率和表观分布容积分别为24.6 L·h^-1和502 L。联合用药中红霉素、五酯胶囊、伏立康唑以及CYP3A5^*3基因型、红细胞比容对TAC的表现清除率均有显著影响。内部验证GOF图、NPDE、Bootstrap结果及外部验证数据均表明模型预测结果可靠。结论本研究在肾移植受者中建立的TAC的群体药代动力学模型,可以成为指导TAC剂量调整的有效工具。

Objective To determine the effect of genetic polymorphisms and drug combinations on tacrolimus metabolism with a population pharmacokinetic(PPK)model,and to assist patients in individualized administration.Methods Totally of 1634 tacrolimus steady-state trough concentration blood samples were collected from 162 adult kidney transplant recipients.The population pharmacokinetic model was established with the nonlinear mixed-effect modeling software NONMEM 7.4.The internal validation was conducted by goodness-of-fit plots(GOF),normalised prediction distribution errors(NPDE)and bootstrap method.Additionally,another 602 trough concentration data from another 56 patients were collected for external validation to evaluate the accuracy and precision of the model by root median square error(RMSE),median prediction error(MPE)and standardised prediction error(SPE).Results A one-compartment model with firstorder absorption and elimination was set up to describe the pharmacokinetics of tacrolimus.The apparent clearance rate and apparent distribution volume of the final model were 24.6 L·h^-1 and 502 L,respectively.CYP3A5^*3 genotype,hematocrit,erythromycin,Wuzhi capsules and voriconazole all had significant effects on the tacrolimus clearance rate.Both the internal validation(including GOF,NPDE,Bootstrap)and the external validation showed that the prediction of the model was reliable.Conclusion The population pharmacokinetic model of TAC in this study can be used as an effective tool to guide TAC dose adjustment in kidney transplant recipients.