拉考沙胺国外儿童群体药动学模型外部验证和精准用药  

External Validation and Precision Drug Use of Pharmacokinetic Model of Lacosamide in Foreign Pediatric Populations

作　　者：陈惠敏 汪洋[2] 王俊 刘智胜[1] CHEN Huimin;WANG Yang;WANG Jun;LIU Zhisheng(Department of Neurology,Wuhan Children's Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430016,China;Department of Pharmacy,Wuhan Children's Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430016,China)

机构地区：[1]华中科技大学同济医学院附属武汉儿童医院神经内科,武汉430016 [2]华中科技大学同济医学院附属武汉儿童医院药学部,武汉430016

出　　处：《医药导报》2025年第1期108-115,共8页Herald of Medicine

基　　金：国家重点研发计划(2016YFC1306202);湖北省科技计划立项项目-儿童神经发育障碍临床医学研究中心(2022DCC020)。

摘　　要：目的采用真实世界收集的病例数据验证国外报道的拉考沙胺儿童群体药动学(PPK)模型的预测性能,同时分析暴露-效应关系并模拟优化给药方案。方法收集64例年龄4~13.42岁癫痫患儿口服拉考沙胺达稳态后的血药浓度数据和临床资料,通过拟合优度图和直观预测检验考察国外模型的预测准确性。分析拉考沙胺给药日剂量或谷浓度与临床疗效的关系,并基于药动学参数采用蒙特卡罗模拟评价和筛选拉考沙胺用于不同体质量分层及联合用药情况下最佳给药剂量方案。结果外部验证结果显示国外儿童PPK模型的预测准确性较好。基于模型采用贝叶斯法得到拉考沙胺单药治疗癫痫儿童的药动学参数分别为:吸收速率常数(k a)=(2.43±0.04)h^(-1),表观分布容积(V d/F)=(22.69±6.00)L,清除率(CL/F)=(1.25±0.27)L·h^(-1),半衰期(t 1/2)=(12.74±2.40)h。临床有效病例日剂量5%~95%分位数分布区间为2.5~6.3 mg·kg^(-1)·d^(-1),谷浓度5%~95%分位数分布区间为1.9~6.7 mg·L^(-1)。模拟结果显示,按该研究推荐的拉考沙胺优化给药方案可提高药物浓度的达标概率,保障治疗的有效性和耐受性。结论该研究验证了拉考沙胺国外儿童PPK模型的预测性能,并基于此模型模拟了优化给药方案,可为临床医生个体化合理用药提供参考。Objective To verify the predictive performance of the population pharmacokinetic(PPK)model of lacosamide in children reported abroad using real-world case data,the exposure-response relationship was analyzed,and the optimal dosing regimen was simulated.Methods The plasma concentration data and clinical data of 64 children with epilepsy aged 4-13.42 years after oral administration of lacosamide reached a steady state were collected,and the prediction accuracy of foreign models was investigated by goodness-of-fit diagram and intuitive prediction test.The relationship between the daily dose or trough concentration of lacosamide and the clinical efficacy was analyzed,and Monte Carlo simulation was used to evaluate and screen the optimal dosing regimen of lacosamide for different body weight stratification and combinations based on pharmacokinetic parameters.Results The external validation results show that the prediction accuracy of the PPK model for children abroad is good.The pharmacokinetic parameters of lacosamide monotherapy in children with epilepsy were as follows:absorption rate constant(k a)=(2.43±0.04)h^(-1),apparent volume of distribution(V d/F)=(22.69±6.00)L,clearance rate(CL/F)=(1.25±0.27)L·h^(-1),half-life(t 1/2)=(12.74±2.40)h.The distribution range of 5%-95%quantile of daily dose of clinically effective cases was 2.5-6.3 mg·kg^(-1)·d^(-1),and the distribution range of 5%-95%of trough concentration was 1.9-6.7 mg·L^(-1).The simulation results showed that the optimized dosing regimen of lacosamide recommended in this study could increase the probability of drug concentration reaching the target and ensure the efficacy and tolerability of treatment.Conclusions The prediction performance of the PPK model of lacosamide in foreign children was verified,and the optimal dosing regimen was simulated based on this model,which can provide a reference for clinicians to individualize and rationalize the use of drugs.

关 键 词：拉考沙胺 药动学模型 量效关系 剂量优化/儿童 

分 类 号：R985[医药卫生—药品] R971.6[医药卫生—药学]