Qiu Xuewen, Dai Qing, Sun Fengjun, Liu Yao, Yang Bo, Xiang Rongfeng, Yu Mingjie, Xiong Lirong, Bi Shanshan, Lu Wei, Chen Yongchuan, Xia Peiyuan
Int J Clin Pharmacol Ther. 2016 May;54(5):362-8. doi: 10.5414/CP202104.
To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.
利用一组健康（非癫痫）受试者建立口服抗癫痫药物唑尼沙胺基于人群的药代动力学模型，并评估个体因素对唑尼沙胺药代动力学的影响。30名健康的年轻成年人（21 - 39岁）被随机分为3个相等的组（男女比例1:1），分别单次服用200mg、300mg或400mg的唑尼沙胺。另外9名受试者（22 - 24岁）每天服用一次300mg的唑尼沙胺，共服用14天，组成多剂量组。在给药前（基线，0小时）和给药后（1 - 300小时）采集静脉血样进行分析，共提供607个样本用于建立药代动力学模型。人群药代动力学分析采用ICON公司的非线性混合效应建模（NONMEM）软件进行。最终模型的验证通过非参数自举法和可视化预测检验进行。唑尼沙胺的药代动力学最好用具有一级消除的二室模型来描述。在最终模型中，清除率（CL）的估计值为23.25L/h，中央室分布容积（Vc）为34.50L，室间清除率（Q）为20.22L/h，吸收速率常数（Ka）为0.026h⁻¹。单剂量给药时外周分布容积（Vp）为1429L，多剂量给药时为1003L。体重是影响CL、Vc、Vp和Q的显著协变量。此外，女性受试者的Q值低于男性受试者。口服唑尼沙胺后的药代动力学可用线性一级消除二室模型描述，这可为唑尼沙胺在中国成年人中的临床应用提供参考。
