基于群体药动学的儿童奥卡西平给药方案优化和漏服药物补救方案研究

目的:建立奥卡西平在儿童群体中的药动学模型，辅助制定个体化给药方案和漏服药物后的补救方案。方法:收集124例4个月~18岁儿童癫痫患者口服奥卡西平后体内主要活性代谢产物羟基卡马西平(MHD)的药物浓度数据和临床资料，采用非线性混合效应建模法建立群体药动学(PPK)模型。应用自举法、预测值校准的直观预测检验(pc-VPC)、正态化预测分布误差检验(NPDE)评价PPK模型的预测性能。基于最终模型参数，模拟不同特征儿童患者的最佳给药方案和不同漏服场景下的补救给药方案。结果:本研究发现奥卡西平在儿童体内的药动学特征符合一级吸收和消除的一房室模型，按标准体质量70 kg成人校正的群体典型值为:吸收速率常数(K_a)=0.83 h^-1，表观分布容积(V_d/F)=16.70 L，清除率(CL/F)=1.92 L·h^-1。体质量是影响V_d/F和CL/F的显著性协变量。自举法、pc-VPC和NPDE检验显示模型预测准度高，稳定性好。模拟结果显示，按本研究推荐的维持方案和漏服后补救方案给药可提高药物浓度的达标概率，保证治疗的安全性和有效性。结论:本研究通过群体药动学研究，制定了不同体质量分层儿童患者的奥卡西平优化给药方案以及漏服药物后的补救方案，可为临床药物治疗决策提供参考。

Investigating the optimum dosing regimens of oxcarbazepine and remedial strategies of dosing omissions in children based on population pharmacokinetics

OBJECTIVE To develop a population pharmacokinetic (PPK) model of oxcarbazepine (OXC) and individualize the dosing regimens of OXC in pediatric patients with epilepsy,and to investigate the remedy schemes of dosing omissions.METHODS Therapeutic drug monitoring samples of 10-hydrocarbamazepine(MHD)-the main active metabolite of OXC and clinical data were collected from 124 aged from 4 months to 18 years pediatric patients with epilepsy. PPK analysis was performed by using a nonlinear mixed effect model. Bootstrap,prediction-corrected visual predictive check (pc-VPC),normalised prediction distribution errors (NPDE) was used to evaluate the predictive performance of PPK model. Based on the final model parameters,we simulated the optimum dosing regimens for pediatric patients with different characteristics and made rational recommendations for the remedy schemes under various scenarios of missed doses.RESULTS The study found that OXC pharmacokinetics in pediatrics obeyed one-compartment model with first-order absorption and elimination. The population typical values corrected by standard body weight 70 kg of adults were as follows:absorption rate constant (K_a)=0.83 h^-1,apparent volume of distribution(V_d/F)=16.70 L,clearance(CL/F)=1.92 L·h^-1. Body weight was a significant covariate affecting V_d/F and CL/F,Bootstrap,pc-VPC and NPDE showed that the PPK model had good predictability and stability. The simulation results showed that the maintenance administration schemes and remedy schemes recommended in this study could improve the probability of reaching standard drug concentration and ensure the safety and effectiveness of treatment.CONCLUSION Our study established PPK model and formulated the optimal administration regimens of OXC and OXC dosing omissions based on different body weight stratifications for pediatric patients,which can provide reference for clinical treatment decision-making.