Retrospective Population Pharmacokinetic Analysis of Levetiracetam in Children and Adolescents with Epilepsy
Retrospective Population Pharmacokinetic Analysis of Levetiracetam in Children and Adolescents with Epilepsy
复制标题
左乙拉西坦在儿童和青少年癫痫患者中的回顾性群体药代动力学分析
作者：
N. Toublanc;M. Sargentini‐Maier;B. Lacroix;P. Jacqmin;A. Stockis
摘要目的：描述左乙拉西坦的药代动力学特征，确定显著的协变量关系，并确定儿童中达到与成人相似血药浓度的剂量。
研究方法：采用非线性混合效应模型分析了5项左乙拉西坦连续治疗试验中228名3个月至18岁癫痫儿童的汇总数据。模拟用于确定达到左乙拉西坦稳态峰和谷血浆浓度的给药方案，这些浓度与接受推荐的连续治疗起始剂量（500 mg，每日两次）的成人中达到的浓度相似。考虑纳入基础模型的协变量为年龄、体重、性别、人种、体表面积（BSA）、体重指数（BMI）、肌酐清除率（CLCR）、左乙拉西坦剂量、按类别（中性、酶诱导剂、抑制剂、诱导剂和抑制剂联合用药）列出的合并抗癫痫药物（AED）和苯二氮卓类药物。
结果：具有一级吸收和消除的一室模型最能表征数据。确定了以下显著协变量：（i）年龄对吸收速率常数（ka）的影响;（ii）体重、剂量、CLCR和伴随酶诱导AED对血浆口服清除率（CL/F）的影响;和（iii）体重对口服给药后表观分布容积（Vd/F）的影响。主要解释协变量为年龄对ka的影响、体重对CL/F和Vd/F的影响以及酶诱导AED对CL/F的影响，其中体重是最具影响力的协变量。对于体重50 kg的儿童，可采用10 mg/kg口服溶液每日两次<50 kg and a 500-mg tablet twice daily in those weighing >给药，或者如果患者喜欢固体制剂，体重<20 kg的儿童可采用10 mg/kg口服溶液每日两次给药，体重20-40 kg的儿童可采用250 mg片剂每日两次给药，体重>40 kg的儿童可采用500 mg片剂每日两次给药。所有这些剂量达到的稳态峰浓度和谷浓度与连续治疗的推荐起始剂量（500 mg，每日两次）在成人中观察到的相似。
结论：儿童左乙拉西坦药代动力学最有影响的协变量是体重。左乙拉西坦10 mg/kg每日两次的起始剂量可确保儿童的暴露量与成人500 mg每日两次的暴露量相同。
AbstractObjective: To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults.
Methods: Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CLCR), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines.
Results: A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (ka); (ii) bodyweight, dose, CLCR and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (Vd/F). The main explanatory covariates were age on ka, bodyweight on CL/F and Vd/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20–40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily).
Conclusions: The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.