A global pharmaceutical company initiative: An evidence-based approach to define the upper limit of body weight loss in short term toxicity studies
A global pharmaceutical company initiative: An evidence-based approach to define the upper limit of body weight loss in short term toxicity studies
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DOI：
10.1016/j.yrtph.2013.04.003
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发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
Robinson, Sally
中科院分区：
文献类型：
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作者：
Chapman, Kathryn;Sewell, Fiona;Robinson, Sally
在动物身上进行短期毒性研究，以提供有关通常在最大耐受剂量 (MTD) 下的主要不良反应的信息。从科学和伦理的角度来看，此类研究非常重要，因为它们用于对潜在候选药物的进展做出决策，并为后续监管研究设定剂量水平。 MTD 通常由临床症状、体重减少和食物消耗等参数确定。然而，这些评估通常是主观的，并且没有公布的标准来指导选择适当的 MTD。即使存在客观测量，例如体重减轻 (BWL)，对于什么水平构成 MTD 也没有达成一致。由国家研究动物替代、精炼和减少中心 (NC3Rs) 牵头的一项由 15 家公司组成的全球倡议共享了毒性研究中 BWL 的数据，以评估对动物和研究结果的影响。 151 项研究的信息已被用于开发短期毒性研究中 BWL 的警报/警告系统。数据分析支持大鼠和狗的短期给药（最多 7 天）BWL 限制为 10%，非人类灵长类动物 (NHP) 的 BWL 限制为 6%。 (C) 2013 作者。由爱思唯尔公司出版。保留所有权利。
Short term toxicity studies are conducted in animals to provide information on major adverse effects typically at the maximum tolerated dose (MTD). Such studies are important from a scientific and ethical perspective as they are used to make decisions on progression of potential candidate drugs, and to set dose levels for subsequent regulatory studies. The MTD is usually determined by parameters such as clinical signs, reductions in body weight and food consumption. However, these assessments are often subjective and there are no published criteria to guide the selection of an appropriate MTD. Even where an objective measurement exists, such as body weight loss (BWL), there is no agreement on what level constitutes an MTD. A global initiative including 15 companies, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), has shared data on BWL in toxicity studies to assess the impact on the animal and the study outcome. Information on 151 studies has been used to develop an alert/warning system for BWL in short term toxicity studies. The data analysis supports BWL limits for short term dosing (up to 7 days) of 10% for rat and dog and 6% for non-human primates (NHPs). (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.