肾病综合征患者他克莫司的群体药动学研究

Population Pharmacokinetics of Tacrolimus in Patients with Nephrotic Syndrome

关键词:  他克莫司  肾病综合征  非线性混合效应模型  群体药动学

Key words:  tacrolimus  nephrotic syndrome  nonlinear mixed effect model  population pharmacokinetics

摘要:

目的 应用非线性混合效应模型NONMEM考察成人肾病综合征患者他克莫司的群体药动学特征。方法 回顾性收集肾病综合征患者51例，246个血药浓度监测数据。以其年龄、性别、体质量、他克莫司日剂量、肝肾功能及合并用药等为协变量，采用具有一级吸收和消除的一室模型拟合数据，并通过自举法和正态化预测分布误差法对模型进行验证。结果 他克莫司的表观清除率（CL/F）为13.9 L·h^-1，表观分布容积（V/F）为382 L，他克莫司日剂量（DD，mg·d^-1）、红细胞压积（HCT）、合并使用五酯胶囊对CL/F有显著影响。模型评价显示该模型及参数估算值可靠稳定，CL/F的最终模型为CL/F=13.9×0.668^WZ×（DD/2）^0.354×（HCT/0.394）^-0.522，其中合并使用五酯胶囊时WZ为1，反之为0。结论 建立的肾病综合征患者口服他克莫司的群体药动学模型能较好地估算患者的群体及个体药动学参数，可为该药的个体化给药方案设计提供参考。

Abstract:

OBJECTIVE To investigate a population pharmacokinetics characteristic of tacrolimus in patients with nephrotic syndrome by using nonlinear mixed effect model NONMEM. METHODS Totally 246 trough concentrations were retrospectively collected from 51 patients with nephrotic syndrome who received tacrolimus. Using age, sex, body weight, daily dose of tacrolimus, liver and kidney function and co-therapy medications as covariates, a one-compartment model with first order absorption and elimination was used to analyze the data, and the model was assessed by using bootstrap and normal prediction distribution error. RESULTS The tacrolimus of apparent clearance(CL/F) and apparent volume of distribution(V/F) was 13.9 L·h^-1 and 382 L, respectively. Daily dose of tacrolimus(DD, mg·d^-1), hematokrit(HCT) and co-administration of Wuzhi capsule had a significant effect on the CL/F. The model evaluation showed that the model and the estimated parameters were reliable and stable. The final model of CL/F was CL/F=13.9×0.668^WZ×(DD/2)^0.354×(HCT/0.394)^-0.522. When combined with Wuzhi capsule, WZ was 1, whereas was 0. CONCLUSION The population pharmacokinetics model of tacrolimus in nephrotic syndrome patients can better estimate population and individual pharmacokinetic parameters, which can provide relevant reference of individualized dosing regimen of tacrolimus.