Tuo Yali, Yu Xiaolong, Li Sichan, Wang Jun, Liu Maochang, Song Xinwen, Ma Jiehui, Wang Yang, Liu Zhisheng, Sun Dan
Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.
Emergency and Critical Care Medical Center, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.
Pharmaceutics. 2025 Jun 23;17(7):813. doi: 10.3390/pharmaceutics17070813.
This study aimed to characterize the pharmacokinetic profiles of clobazam (CLB) and its active metabolite, N-desmethylclobazam (N-CLB), by establishing a population pharmacokinetic (PPK) model in Chinese children with epilepsy to propose individualized dosing regimens that achieve better clinical outcomes. : This study examined plasma samples collected from 103 pediatric patients with refractory epilepsy undergoing CLB treatment. The plasma concentrations of CLB and its active metabolite N-CLB were measured. The developmental characteristics, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators of the children with epilepsy were considered potential factors affecting the pharmacokinetic characteristics of CLB and N-CLB and analyzed using a PPK modeling approach. : A total of 156 samples were attained for PPK model development. The pharmacokinetic profiles of CLB and N-CLB were described using a tandem one-compartment model with first-order elimination. Body weight and CYP2C19 genotype showed statistical significance for CLB and/or N-CLB clearance. The N-CLB/CLB metabolic ratios of AUC, C, and C in a steady state were as follows: normal metabolizers (NMs) < intermediated metabolizers (IMs) < poor metabolizers (PMs). The final model achieved good prediction performance and stability. Monte Carlo simulations demonstrated that the trough concentrations of CLB and N-CLB in children with epilepsy could reach satisfactory target values under varying dose regimens in CYP2C19 NMs and IMs, whereas there was a failure to achieve the desired trough concentrations of CLB and N-CLB simultaneously in CYP2C19 PMs due to the accumulation of N-CLB. : Body weight and CYP2C19 genotype had an impact on CLB and/or N-CLB clearance in children with epilepsy. To ensure safe treatment, it is recommended to use the concentration of N-CLB as the target indicator for therapeutic drug monitoring and dose adjustments in CYP2C19 PMs. These results provide evidence for guiding the precise use of CLB.
本研究旨在通过建立中国癫痫儿童的群体药代动力学（PPK）模型，来描述氯巴占（CLB）及其活性代谢物N -去甲基氯巴占（N - CLB）的药代动力学特征，以提出能实现更好临床疗效的个体化给药方案。本研究检测了103例接受CLB治疗的难治性癫痫儿科患者的血浆样本，测定了CLB及其活性代谢物N - CLB的血浆浓度。将癫痫患儿的发育特征、CYP2C19基因型、合并用药以及肝肾功能指标视为影响CLB和N - CLB药代动力学特征的潜在因素，并采用PPK建模方法进行分析。共获取156个样本用于PPK模型构建；采用具有一级消除的串联单室模型描述CLB和N - CLB 的药代动力学特征；体重和CYP2C19基因型对CLB和/或N - CLB清除率具有统计学意义；稳态下N - CLB/CLB代谢比的AUC、Cmax和Cmin如下：正常代谢者（NMs）＜中间代谢者（IMs）＜慢代谢者（PMs）；最终模型具有良好的预测性能和稳定性；蒙特卡洛模拟表明，在不同剂量方案下，CYP2C19 NMs和IMs癫痫患儿中CLB和N - CLB的谷浓度可达到满意的目标值，而在CYP2C19 PMs中，由于N - CLB的蓄积，无法同时达到CLB和N - CLB所需的谷浓度。体重和CYP2C19基因型对癫痫患儿CLB和/或N - CLB清除率有影响；为确保安全治疗，建议将N - CLB浓度作为CYP2C19 PMs治疗药物监测和剂量调整的目标指标；这些结果为指导CLB的精准使用提供了依据。
