Predicting the Pharmacokinetic Characteristics of Edaravone Intravenous Injection and Sublingual Tablet Through Modeling and Simulation

• Published in: Clinical therapeutics Vol. 42; no. 3; pp. 428 - 438
• Main Authors: Chen, Xia, Sun, Zhuo, Wang, Jiaqing, Liang, Wu, Zhao, Xingquan, Wang, Yilong, Wang, Yongjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2020; Elsevier Limited
• Subjects: acute ischemic stroke; ALS; Amyotrophic lateral sclerosis; Bioavailability; Bioequivalence; Dosage; Drug dosages; Hospitals; Internal Medicine; Intravenous administration; Ischemia; Laboratories; Medical screening; Oral administration; Oxidative stress; Pharmacokinetics; Regulatory approval; simulation; Software; Stroke; Beijing China; China; Japan; ALS; model; acute ischemic stroke; simulation; bioequivalence
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2020.01.006

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.