Jullien Vincent, Chhun Stéphanie, Rey Elisabeth, Dulac Olivier, Tod Michel, Chiron Catherine, Pons Gérard
Inserm U1129, Paris, France,
Clin Pharmacokinet. 2015 May;54(5):527-36. doi: 10.1007/s40262-014-0223-5.
The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose.
Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM(®) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg.
The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB).
This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.
本研究旨在描述接受标准司替戊醇/丙戊酸/氯巴占联合治疗的德雷维特综合征患儿中氯巴占及其活性代谢物N-去甲基氯巴占（N-CLB）的药代动力学，并确定该人群中每日两次、每次0.2mg/kg常用剂量下氯巴占和N-CLB的血药浓度。
35例癫痫患儿纳入一项前瞻性群体药代动力学研究（使用NONMEM®软件）。每位患者采集4份血样。针对12,000名体重在10至60kg之间的理论儿童，模拟了氯巴占和N-CLB的血浆浓度-时间曲线下面积（AUC）和谷浓度（C trough）值。
氯巴占的药代动力学可用具有一级吸收和消除的单室模型描述，N-CLB的生成和消除也是一级过程。氯巴占的表观总清除率（CL/F）和分布容积（V CLB/F）以及N-CLB的消除速率常数（Kem）通过异速方程与体重相关。群体平均估计值（个体间变异百分比）为：CL/F为1.23L/h（29%），V CLB/F为39.1L（18%），Kem为0.0706h-1（26%）。当体重从10kg增加到60kg时，氯巴占和N-CLB的AUC值增加了100%，模拟的C trough值高于目前公认的目标值（氯巴占为0.03 - 0.3mg/L，N-CLB为0.3 - 3mg/L）。
这是首个针对癫痫患儿中氯巴占和N-CLB的同步药代动力学模型。提供了司替戊醇治疗的德雷维特综合征患儿中氯巴常规治疗药物监测的指示性值。氯巴占和N-CLB暴露量与体重相关变化的可能后果应进一步评估。
