摘要
目的建立肾病综合征患儿体内他克莫司群体药动学(PPK)模型,考察五酯胶囊对其药动学的影响。方法收集198例肾病综合征患儿体内他克莫司血药谷浓度数据和临床资料,应用NLME程序进行PPK分析,考察各种因素对他克莫司药动学特征的影响。采用拟合优度作图、自举验证、正态化预测分布误差和直观预测检验法评价最终模型的预测性能,并利用蒙特卡洛模拟法探索最佳给药方案。结果PPK分析显示他克莫司具有一房室模型特征,患儿体重、天冬氨酸转氨酶和联用五酯胶囊是影响其清除率的显著因素。最终模型药动学参数的群体典型值分别为:清除率5.89 L·h^-1,表观分布容积88.41 L。最终模型稳定且预测性能可靠。模拟结果显示他克莫司(35μg·kg^-1,bid)单药治疗和他克莫司(6μg·kg^-1,bid)联用五酯胶囊为最优给药方案。结论本研究成功建立了肾病综合征患儿他克莫司PPK模型,量化了五酯胶囊对他克莫司药动学的影响,模拟结果显示五酯胶囊能在保证治疗安全有效的同时大幅降低他克莫司的给药剂量。
AIM To establish a population pharmacokinetic(PPK)model of tacrolimus in Chinese children with nephrotic syndrome,and to investigate the effect of Wuzhi capsules on the pharmacokinetics of tacrolimus.METHODS The trough concentrations and clinical data of 198 pediatric patients with nephrotic syndrome were collected.To investigate the influence of various factors on the pharmacokinetic characteristics of tacrolimus,PPK analysis was carried out by NLME program.Goodness-of-fit plots,nonparametric bootstrap,normalized prediction distribution errors and visual predictive check were employed to evaluate the final model.The Monte Carlo method was conducted for exploration of optimal dosing regimen.RESULTS The results of PPK analysis showed that the pharmacokinetics of tacrolimus could be best described by a one compartment model with first order absorption and elimination along with body weight,aspartate aminotransferase and combination with Wuzhi capsules as significant covariates.The typical values of pharmacokinetic parameters were as follows:CL=5.89 L·h^-1,Vd=88.41 L.The validation results showed that the final model was stable and the prediction performance was reliable.Simulations demonstrated that the dosage regimens of tacrolimus(35μg·kg^-1,bid)alone and tacrolimus(6μg·kg^-1,bid)combined with Wuzhi capsules were optimal.CONCLUSION In the current study,PPK model of tacrolimus is successfully established in children with nephrotic syndrome,and the effect of Wuzhi capsules on the pharmacokinetics of tacrolimus is quantified.The simulation results show that Wuzhi capsules could significantly reduce the dose of tacrolimus while ensuring the safety and effectiveness of treatment.
作者
李思婵
徐华
叶琦
汪洋
伍三兰
曹鹏
LI Si-chan;XU Hua;YE Qi;WANG Yang;WU San-lan;CAO peng(Department of Pharmacy,Wuhan Children’s Hospital/Wuhan Maternal and Child Healthcare Hospital,Tongji Medical College,Huazhong University of Science&Technology,Wuhan HUBEI 430016,China;Department of Pharmacy,Union Hospital,Tongji Medical College,Huazhong University of Science&Technology,Wuhan HUBEI 430022,China)
出处
《中国新药与临床杂志》
CAS
CSCD
北大核心
2020年第8期477-485,共9页
Chinese Journal of New Drugs and Clinical Remedies
基金
国家自然科学基金青年项目(81600123)
武汉市卫生计生委青年项目(WX17Z13)。
关键词
儿童
他克莫司
五酯胶囊
肾病综合征
群体药动学
蒙特卡洛模拟
child
tacrolimus
Wuzhi capsules
nephrotic syndrome
population pharmacokinetics
Monte Carlo simulation
