联用五酯胶囊的成人肾病综合征患者他克莫司PopPK模型建立及给药方案优化

Establishment of Tacrolimus PPK Model and Optimization of Dosage Regimen in Adult Nephritic syndrome Patients

目的以合用五酯胶囊剂量为主要考查因素,建立中国成人肾病综合征患者口服他克莫司的群体药动学(population pharmacokinetics,PopPK)模型。方法收集我院2018年10月至2020年4月,年龄为18岁及以上接受他克莫司治疗的肾病综合征患者(n=72)临床信息。使用非线性混合效应模型确定个体间变异影响因素并建立群体药动学模型。根据群体药动学参数进行10000次蒙特卡罗模拟,优化推荐给药剂量并对22例患者进行临床验证。结果他克莫司的平均表观清除率(CL/F)为13.5 L·h^(-1)。增加五酯胶囊剂量、血浆白蛋白和红细胞数增加均降低CL/F,合用糖皮质激素患者他克莫司的CL/F比未合用组高2.08 L·h^(-1)。经22例患者的98个血药浓度监测点验证,模型模拟推荐的给药方案使患者血药浓度达标率由15.8%升至85.0%。结论建立了他克莫司在成人肾病综合征患者体内的群体药动学模型,更好的描述了五酯胶囊剂量与他克莫司体内代谢的量效关系,该模型可用于选择更经济合理的给药方案,以达到理想的血药浓度。

OBJECTIVE To establish a population pharmacokinetics(PopPK)model of tacrolimus in Chinese adult nephrotic syndrome patients,and take the combined dose of Wuzhi capsules as the main variable.METHODS Clinical information of nephrotic syndrome patients(≥18 years old)who received tacrolimus treatment in our hospital from October 2018 to April 2020 was collected.The population pharmacokinetic approach and the influencing factors of inter-individual were analyzed using nonlinear mixed effect model(NONMEM).The dosage was optimized based on the results of 10000 Monte Carlo simulations and clinical validation was performed in 22 patients.RESULTS The mean apparent clearance rate(CL/F)of tacrolimus was 13.5 L·h^(-1).Increasing the dose of Wuzhi capsules,plasma albumin,and red blood cell will decrease CL/F.The CL/F with glucocorticoid combination was 2.08 L·h^(-1) higher than that in the untreated group.The drug regimen was verified at 98 monitoring points of blood drug concentration in 22 patients,which increased the compliance rate from 15.8%to 85.0%.CONCLUSION A population pharmacokinetic model of tacrolimus in adult nephrotic syndrome is established.The model better describes the dose-response relationship between the dose of Wuzhi capsules and tacrolimus metabolism,and it can be used to select more economical and rational drug delivery regimen to achieve the ideal blood drug concentration.