成人慢性肾小球肾炎患者他克莫司群体药动学研究

Population pharmacokinetics of tacrolimus in adult patients with chronic glomerulonephritis

目的:建立成人慢性肾小球肾炎患者他克莫司群体药动学(population pharmaco-kinetics,PPK)模型。方法:收集55例慢性肾小球肾炎患者的268个他克莫司血药浓度数据。采用非线性混合效应模型考察CYP3A5基因型、体质量、年龄、实验室指标、合并用药等对他克莫司药动学参数的影响,建立他克莫司PPK模型,并通过拟合优度诊断、Bootstrap自举法及正态预测分布误差法对模型进行验证。结果:他克莫司表观清除率及表观分布容积的群体典型值分别为13.8L·h-1和733L,CYP3A5基因型和合并用药五酯胶囊对他克莫司清除率具有显著影响。经验证他克莫司PPK模型稳定有效。结论:首次建立成人慢性肾小球肾炎患者他克莫司PPK模型,可为慢性肾小球肾炎患者的他克莫司个体化给药提供参考。

OBJECTIVE To establish a population pharmacokinetic model of tacrolimus in adult patients with chronic glomerulonephritis.METHODS Totall 268 tacrolimus concentrations were collected from 55 patients with chronic glomerulonephritis. The population pharmacokinetic model of tacrolimus, which was used to investigate the effect of CYP3A5 genotype, co-therapy drugs, physiological and pathological factors on pharmacokinetic parameters, was established using NONMEM. The validation and reliability of final PPK model were evaluated by diagnosis, Bootstrap and NPDE verification.RESULTS The population estimate values of apparent clearance and apparent volume were 64.7 L·h^-1 and 832 L, respectively. CYP3A5 genotype and co-therapy with Wuzhi capsules had significant effects on the clearance. The goodness of fit diagnosis, Bootstrap, NPDE showed that the final model was stable and effective.CONCLUSION This is the first study of tacrolimus in adult patients with chronic glomerulonephritis, which can be used for individualized drug therapy of tacrolimus.