Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4-to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate
Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4-to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate
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DOI：
10.1016/j.eplepsyres.2006.12.005
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发表时间：
2007-04-01
影响因子：
2.2
通讯作者：
Lu, Zhihong (Sarah)
中科院分区：
文献类型：
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作者：
Fountain, Nathan B.;Conry, Joan A.;Lu, Zhihong (Sarah)
目的：评价左乙拉西坦及其主要代谢物L057在部分发作性癫痫患儿中的多剂量药代动力学，并确定辅助用药卡马西平或丙戊酸是否对其有影响。血浆和唾液中左乙拉西坦浓度的相关性，并评估其安全性和临床反应。方法：设计为开放标签、多中心研究。21名癫痫儿童（4-12岁）服用卡马西平（13）或丙戊酸(8)，辅助服用左乙拉西坦。左乙拉西坦起始剂量为20mg/（kg天），每2周滴定至40mg /（kg天），然后60mg/（kg天）。每2周结束时测定12小时药代动力学。根据每周部分发作频率和整体评估量表评估疗效。结果：左乙拉西坦口服给药后吸收迅速，中位t（max）为0.5 h， C-max和AUC（(0-1 2)）在剂量范围内呈剂量正比增加；t(1/2) = 4.9 h。左乙拉西坦和ucb L057的药代动力学与同期用药卡马西平或丙戊酸无显著差异；与丙戊酸相比，卡马西平组的清除率仅提高了7-13%，AUC仅降低了15-24%。左乙拉西坦对卡马西平和丙戊酸没有影响。唾液和血浆浓度密切相关。在打算治疗的人群中，43%的受试者（n = 21）癫痫发作频率下降了50%或更多，在基线时癫痫发作的受试者中，这一比例为56% （n = 16）。根据研究者和家长/监护人的全球评估量表评分，分别有80%和75%的患者出现显著或中度改善。左乙拉西坦耐受性良好。结论：左乙拉西坦在儿童体内具有简单的药代动力学，具有快速吸收和剂量比例动力学。在接受卡马西平和丙戊酸治疗的受试者之间观察到微小但不具有临床相关性的差异，表明通常没有必要进行显著的剂量调整。这证实了先前的评估，即儿童的左乙拉西坦清除率高于成人，需要在mg/kg的基础上给儿童更高的剂量，并表明无论基线治疗如何，它都是部分发作性癫痫儿童的有用附加治疗。(c) 2007 Elsevier B.V.版权所有
Purpose: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response.Methods: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20mg/(kg day) and titrated at 2-week intervals to 40 and then 60mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale.Results: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C-max and AUC((0-1 2)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n = 21) and in 56% of those with seizures at baseline (n = 16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated.Conclusion: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy. (c) 2007 Elsevier B.V. All rights reserved.