【作者】 王琛瑀； 丁俊杰； 焦正；

【Author】 Chen-yu WANG;Jun-jie DING;Zheng JIAO;Huashan Hospital of Fudan University;Children’s Hospital of Fudan University;

【机构】 复旦大学附属华山医院； 复旦大学附属儿科医院；

【摘要】 目的:癫痫是儿童神经系统常见的慢性发作性疾病,抗癫痫药物治疗是目前主要的治疗手段,而药物依从性是癫痫治疗过程的重要问题。当依从性不佳时设计合理的补救给药方案,对于控制癫痫发作,提高疗效具有显著的临床意义。丙戊酸(VPA)是儿童临床最为常用的一线抗癫痫药物,本研究以现今已发表的6篇儿童VPA群体药动学报道为基础,采用蒙特卡罗模拟评估依从性不佳对VPA药动学的影响以及制定相应的补救给药方案。方法:按照癫痫患儿VPA日剂量20-40 mg/kg,以典型病例常用的VPA给药方案(120,240,500 mg q12h;500,750 mg qd)为基础,涵盖的体重范围为6-40 kg,设计多种延迟服药或漏服药场景。以已报道的癫痫患儿VPA群体药动学模型和群体药动学参数为基础,采用蒙特卡罗模拟5000名患者在不同场景下的VPA血药浓度时间数据。以90%的血药浓度波动范围为个体有效治疗范围,评估不同延迟服药或漏服药情况下对VPA药动学的影响,并以此设计相应的补救给药方案。结果:随延迟服药时间的延长,VPA谷浓度低于治疗范围的风险呈升高趋势;补救给药剂量呈日剂量和延迟时间依赖性,不同给药方案的补救剂量有所不同。基于以上分析,制定了癫痫患儿VPA糖浆剂120～240 mg q12h和缓释片500,750 mg qd以及500 mg q24h方案的延迟服药或漏服药的补救给药方案。在100～300 mg q12h剂量范围内,若延迟服药0～4 h,则应立即给予1个剂量的补救剂量;如延迟4～8 h或8～12 h,则应减少补救剂量,分别给予2/3和1/2个剂量即可;如漏服1次或2次药物,则在下个计划给药时间给予1.5或2个剂量的补救剂量。讨论:蒙特卡罗法为制定依从性不佳时的补救剂量推荐方案提供了强有力的方法。本研究基于群体药动学原理,首次较为完整地考察了癫痫患儿依从性不佳时的血药浓度变化、计算了补救剂量方案,供临床参考。更多还原

【Abstract】 Objective:Epilepsy is a common chronic neurological children disease.The main treatment is the antiepileptic drug therapy,and medication compliance is a severe issue during the treatment of epilepsy.Valproic acid(VPA) is the most commonly used first-line pediatric trials of anti-epileptic drugs,this study aims to investigate the effects of delayed and missed doses(poor compliance) on the pharmacokinetics of valproic acid(VPA) in epileptic children using Monte Carlo simulation.Methods:VPA time-concentration profiles in various scenarios are generated on epileptic children using Monte Carlo simulation,based on five published population pharmacokinetic studies.The scenarios include 5000 simulated patients given multiple doses of VPA that ranged from 120 mg to 500 mg every 12 h or 500 mg and 750 mg once a day.The Individual therapeutic range of VPA which is defined as 90% VPA concentration range for each scenario is estimated to assess the effects of delayed or missed doses and to design corresponding rescue regimens.Results:The risk for a sub-therapeutic range of VPA increase in a dose-dependent manner in both one and two times daily regimens when delayed or missed doses occurred.The effects of poor compliance are less prominent on the lower daily doses compared with those on the higher daily doses.Within 100～300 mg q12 h dose range,if drug administration delayed 0～4 h,a remedy dose should be given immediately;if delayed 4～8 h or 8～12 h,the dose should be 2/3 or 1/2 doses,respectively;if missed medication once or twice,patient should take 1.5 or 2 doses at the next schedluled dosing time.Conclusion:Children with epilepsy should take the delayed doses as soon as possible when the delay occured,and partial missed doses should be taken at the next scheduled time.更多还原