Exploratory drug safety: A discovery strategy to reduce attrition in development
Exploratory drug safety: A discovery strategy to reduce attrition in development
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DOI：
10.1016/j.vascn.2009.04.194
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发表时间：
2009-07-01
影响因子：
1.9
通讯作者：
Hunter, John
中科院分区：
文献类型：
--
作者：
Bass, Alan S.;Cartwright, Mark E.;Hunter, John
对制药业来说，识别具有最大希望的安全和有效治疗的新分子仍然是一个持续的挑战。这导致业界实施战略，以便在发现阶段确定最有希望的候选人，并通过发展安全和迅速地促进他们的进步。在发现阶段对潜在的可靠性质的测试包括对主要制药领域的评估；导致失败的药物的物理和药物性质、药物代谢和药代动力学特征、各种安全终点，包括开发前的安全药理学、一般毒理学和遗传毒理学，以及询问反屏幕数据以确定目标外的亲和力(即受体、离子通道、转运体、激酶等)。这引起了人们的担忧。在许多值得关注的重要领域中，主要器官系统的潜在毒性是。为了减轻这一担忧，所采取的一项战略是在推荐开发之前确定候选药物的突出毒理学特性。这些发现研究的结果允许在花费典型的开发资源和时间之前排除候选人。此外，发现阶段毒理学研究用于解决另一种分子的研究可能产生的关键问题，治疗靶点已被转基因的临床前模型的表型特征，或因其他研究而引起的担忧。重要的是，赞助商将利用探索性药物安全性研究的结果来判断与继续追求潜在的开发候选药物相关的潜在风险。在许多方面，发现中的临床前毒理学调查服务于确定最有希望进入开发和注册的候选对象的重要目标。(C)2009年，爱思唯尔公司出版。
Identification of novel new molecules which hold the greatest promise of safe and effective therapies remains a continuous challenge to the pharmaceutical industry. This has led the industry to implement strategies for identification of the most promising candidates during the discovery phase and for their safe and expeditious advancement through development. Testing for potential liable properties in the discovery phase has included the evaluation of major areas of pharmaceutics; that have led to failure such as its physical and pharmaceutical properties, drug metabolism and pharmacokinetic characteristics, various safety endpoints including pre-development safety pharmacology, general toxicology and genetic toxicology and interrogation of counter-screen data to identify off-target affinities (i.e., receptors, ion channels, transporters, kinases, etc.) that pose a concern. Amongst the many important areas of concern is the potential for toxicities of the major organ systems. To mitigate this concern, a strategy pursued is to identify the prominent toxicological properties of the candidate prior to its recommendation for development. The results of these studies in discovery allow exclusion of the candidate before the expenditure of resources and time typical of development. In addition, the discovery phase toxicology studies serve to address key questions that may have arisen from the study of another molecule, the phenotypic profile from pre-clinical models where the therapeutic target has been genetically modified or concerns that have been raised as a result of other investigations. Importantly, the results of the exploratory drug safety studies will be used by the sponsor to judge the potential risks associated with continued pursuit of a potential development candidate. In many ways, pre-clinical toxicological investigations in discovery serve the important objective of identifying the most promising candidates to progress into development and onto registration. (C) 2009 Published by Elsevier Inc.