左乙拉西坦儿童生理发育药动学模型的建立和剂量优化

The physiological development pharmacokinetic model and dosing optimization oflevetiracetam in children

目的:探讨生理发育因素对左乙拉西坦(LEV)在儿童体内药动学特征的影响,评价和优化LEV给药剂量,促进个体化用药。方法:根据203例0.42~15岁癫痫患者的LEV血药浓度及相关临床资料建立群体药动学模型,考察生理发育因素对LEV药动学参数的影响方式和强度。基于模型,模拟和评价不同体质量和年龄段的儿童患者的LEV给药方案。结果:LEV在儿童体内的药动学特征符合一级吸收和消除的一室模型。在本研究中,LEV的表观分布容积和清除率的群体典型值经过体质量矫正后分别为0.54 L·kg^(-1)和0.082 L·h^(-1)·kg^(-1)。年龄和体质量对LEV在儿童体内的清除率具有显著影响,可以用指数不固定的年龄成熟模型来表征上述关系。模拟结果显示,为了达到LEV的目标谷浓度范围,7.5~15 kg(0.6~3岁)、15~35 kg(3~10岁)和35~55 kg(10~15岁)的患者分别应采用的最优方案为20 mg·kg^(-1)bid、15 mg·kg^(-1)bid和10 mg·kg^(-1)bid。给予体质量矫正剂量相同的LEV时,高年龄段儿童的谷浓度水平更高。结论:本研究成功建立了LEV在儿童群体中的生理发育药动学模型,定量阐述了生理发育因素对LEV药动学的影响,可为不同发育程度的患者的个体化用药提供帮助。

OBJECTIVE To study the influence of physiological development factors on the pharmacokinetic(PK)characteristics of levetiracetam(LEV)in children,to optimize the dose of LEV,thus promoting the individualized medication.METHODS A population PK model was established based on LEV serum concentrations and related clinical data from 203 children with epilepsy aged 0.42 to 15 years to investigate the influence mode and intensity of physiological development factors on LEV PK parameters.According to the final model,the dosing regimens were evaluated and optimized for children with different weight and age.RESULTS The PKs of LEV in children was described by a one-compartment model with first-order absorption and elimination.In this study,the population typical values of weight-normalized apparent distribution volume and clearance were 0.54 L·kg^(-1)and 0.082 L·h^(-1)·kg^(-1),respectively.Age and weight had significant influences on the clearance of LEV in children,which was performed by an age-maturation model with variable index.The simulation results showed that,to achieve the target trough concentration range of LEV,the optimal dosing regimens for children weighting(or aged)7.5~15 kg(0.6~3 years),15~35 kg(3~10 years),and 35~55 kg(10~15 years)were 20 mg·kg^(-1)bid,15 mg·kg^(-1)bid,and 10 mg·kg^(-1)bid,respectively.Moreover,under the same weight-normalized dose of LEV,the trough concentration level was higher in the older-age children.CONCLUSION In this study,the physiological development PK model of LEV in children was successfully established,and the influence of development factors on the PKs of LEV was described in details,which is helpful to the individualized medication of pediatric patients with different maturation levels.