用NONMEM法建立中国成年患者服用地高辛群体药动学模型

Population Pharmacokinetics of Digoxin in Chinese Adult Patients by NONMEM

目的建立中国成年人中服用地高辛患者的群体药动学(PPK)模型,促进个体化给药。方法收集155名长期规律服用地高辛患者的262例次稳态地高辛的测定结果以及相关临床数据。应用NONMEM软件求算PPK参数值,建立基本模型和最终模型。运用内部验证法,验证模型的可靠性。结果地高辛达到稳态时,其PPK模型符合口服吸收一室模型。地高辛体内清除和患者血清肌酐浓度、体重、是否有合并用钙离子拮抗剂(CCB)、螺内酯(SPR)有关。最终模型可表达为:CL/F=9.33×0.512(SCR/119.1)×[1+0.017×(Weight-61.2)]×(1-0.21×CCB)×(1-0.19×SPR)L·kg-1·h-1。Ka=1.54h-1;Vd/F=187L。经内部验证法验证,本模型稳定、可靠。新取5个地高辛数据应用本模型进行预测,预测结果与临床实际监测结果相符较好。结论用NONMEM软件成功建立中国成年人服用地高辛的PPK模型。

OBJECTIVE To establish population pharmacokinetic model of Digoxin in Chinese adult patients, and set up individualized dose regimen by use of individual pharmacokinetic parameters estimated through the model. METHODS 262 Sparse digoxin serum concentrations were collected from 155 adult patients. Basic models and final models of digoxin were developed by NONMEM software and population pharmacokinetic parameters were acquired. RESULTS Population pharmacokinetic model of digoxin was described as one-compartment model. The serum creatinine level, body weight and coadministration of the calcium antagonist （CCB） or spironolactone （SPR） affected the clearance rate of digoxin concentrations in serum.The parameters of final model of digoxin were as follows： CL/F=9.33 × 0.512^（SCR/119.1） × [1＋0.017 × （WEIGHT-61.2）] × （1- 0.21XCCB） ×（1-0.19×SPR） L·kg^-1·h^-1. Ka=1.54 h^-1; Vd/F=187 L. The model was stable and reliable by bootstrap. Good prediction results of digoxin of 5 extra patients were obtained. CONCLUSION Population pharmacokinetic models of digoxin in Chinese adult patients were built successfully by NONMEM software.