Predicting the Pharmacokinetic Characteristics of Edaravone Intravenous Injection and Sublingual Tablet Through Modeling and Simulation |
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| Institution: | 1. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China;2. Phase I Unit, Beijing Tiantan Hoapital, Capital Medical University, Beijing, PR China;3. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China;4. Changsha VALS Technology Co Ltd, Hunan, PR China;1. Department of General Medicine, Affiliated Hospital of Zunyi Medical University, Guizhou, China;2. Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical University, Affiliated Hospital of Zunyi Medical University, Guizhou, China;3. School of Management, Zunyi Medical University, Guizhou, China;4. Evidence-Based Medicine Research Centre, Jiangxi University of Traditional Chinese Medicine, Jiangxi, China;5. Grade 2017 Students, Zunyi Medical University, Guizhou, China;6. Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Guizhou, China;7. Department of Nephropathy, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China;8. Department of Oncology, Lishui People''s Hospital, Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China;1. Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA, USA;2. Department of Internal Medicine, Tufts University School of Medicine, Boston, MA, USA;1. Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea;2. Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea;1. Université Bordeaux Segalen, Bordeaux 33076, France;1. Department of Neurology, Medical University of Warsaw, Warsaw, Poland;2. Disease Research Group, Medical University of Warsaw, Warsaw, Poland |
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| Abstract: | PurposeEdaravone 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.MethodsThe 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.FindingsThe 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.ImplicationThe 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. |
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| Keywords: | acute ischemic stroke ALS bioequivalence model simulation |
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