Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA.
Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA.
Eur J Drug Metab Pharmacokinet. 2021 May;46(3):395-404. doi: 10.1007/s13318-021-00678-0.
Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications.
The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine.
Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine.
A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C) was within ± 25%.
The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.
维索利嗪是一种电压和使用依赖性钠离子通道阻滞剂，目前正在开发用于治疗各种神经性疼痛适应症。
本工作的目的是建立群体药代动力学模型，并评估各种协变量对维索利嗪药代动力学参数的影响。
纳入分析的血浆浓度-时间数据来自 12 项 1 期或 2 期研究。这些数据是在健康志愿者和患者单次或多次给予维索利嗪后获得的。采用单室和双室药代动力学模型作为基本结构药代动力学模型进行评价。一旦建立了基础/全模型，就采用逐步向后消除法（α=0.001）评估选择协变量的纳入。采用可视化预测检查（VPC）评估模型的预测能力。最终模型用于评估协变量对维索利嗪暴露的影响。
共纳入 465 例受试者的 10263 个药代动力学样本进行分析。维索利嗪的药代动力学特征采用双室模型加两个转运吸收室和一级消除过程进行描述。VPC 也验证了模型的预测能力。最终模型纳入了年龄、体重和卡马西平合并用药对清除率、体重对中央分布容积、食物对吸收速率常数和制剂以及日本种族对生物利用度的影响。确定的协变量均无临床相关影响，因为对曲线下面积（AUC）和最大血浆浓度（C）的影响在±25%范围内。
该模型很好地描述了维索利嗪的药代动力学特征，健康受试者和患者的维索利嗪暴露情况相当。评估的协变量均对维索利嗪的药代动力学无临床相关影响。
