China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; Phase I Unit, Beijing Tiantan Hoapital, Capital Medical University, Beijing, PR China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China.
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; Phase I Unit, Beijing Tiantan Hoapital, Capital Medical University, Beijing, PR China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China.
Clin Ther. 2020 Mar;42(3):428-438. doi: 10.1016/j.clinthera.2020.01.006. Epub 2020 Feb 7.
Edaravone is a free-radical scavenger with relatively favorable properties of brain penetration. It has been approved for the indications of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). This study aimed to establish a pharmacokinetic (PK) model to fit the PK profile of edaravone after a single sublingual (SL) dose of a novel edaravone tablet and single IV infusion of injectable edaravone in healthy Chinese volunteers participating in a bioavailability study. The model is expected to be useful for predicting the concentration-time profiles of edaravone following different dosing regimens in a healthy Chinese population. The purposes were to identify an optimal dose and dosing regimen for the new SL formulation and to support future clinical exploration of this tablet product in its approved indications and other therapeutic fields being developed.
The PK profiles after a single SL dose or IV infusion of edaravone 30 mg can be well described by a 3-compartment linear disposition model, on which a first-order absorption model with a lag time and a parameter for bioavailability was incorporated to fit the absorption phase of the SL dose. Performance of these PK models was evaluated for goodness of fit, residual trends, visual predictive checks, as well as precision of model predictions against external data. The validated models were employed for simulating the PK profiles of edaravone after a single SL dose of 60 mg and IV infusion of 60 mg for 60 min.
The resultant estimates support the possibility and feasibility of demonstrating bioequivalence between an SL administration of edaravone 60 mg and the currently approved dosing regimen for ALS (ie, 60 mg IV over 60 min) once per day. The calculation of sample size suggested that the requirement for subject number was acceptable considering the general capacity of a Phase I study center, and so were the procedures defined in the protocol.
The models can be further applied to simulate favorable concentration-time profiles in diseases with different underlying courses of oxidative stress, and hence facilitate the optimization of current dosing regimens.
依达拉奉是一种具有良好脑穿透特性的自由基清除剂。它已被批准用于急性缺血性脑卒中（acute ischemic stroke）和肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS）的治疗。本研究旨在建立一个药代动力学（pharmacokinetic，PK）模型，以拟合健康中国志愿者参加生物利用度研究时单次舌下（sublingual，SL）给予新型依达拉奉片和单次静脉输注依达拉奉注射液后的 PK 特征。该模型有望用于预测健康中国人群中不同给药方案下依达拉奉的浓度-时间曲线。目的是为新型 SL 制剂确定最佳剂量和给药方案，并为该片剂产品在已批准适应症和其他正在开发的治疗领域的未来临床探索提供支持。
单次 SL 剂量或 IV 输注依达拉奉 30mg 的 PK 特征可以很好地用 3 室线性处置模型描述，该模型中包含一个带有滞后时间和生物利用度参数的一级吸收模型，用于拟合 SL 剂量的吸收相。通过拟合优度、残差趋势、可视化预测检查以及模型预测对外部数据的精度来评估这些 PK 模型的性能。验证后的模型用于模拟单次 SL 剂量 60mg 和 IV 输注 60mg（60 分钟）后的依达拉奉 PK 特征。
结果支持在每日一次的情况下，SL 给予依达拉奉 60mg 与目前批准的 ALS 给药方案（即 60mg IV 输注 60 分钟）之间具有生物等效性的可能性和可行性。根据 I 期研究中心的一般能力计算出的样本量需求是可以接受的，方案中定义的程序也是如此。
该模型可进一步应用于模拟不同氧化应激基础疾病的有利浓度-时间曲线，从而有助于优化当前的给药方案。
