NOEL和NOAEL：对最近进行的安全药理学研究样本中提及的回顾性分析。,Journal of Pharmacological and Toxicological Methods

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NOEL和NOAEL：对最近进行的安全药理学研究样本中提及的回顾性分析。
Journal of Pharmacological and Toxicological Methods ( IF 1.3 ) Pub Date : 2019-06-17 , DOI: 10.1016/j.vascn.2019.106597
Theodore J Baird ₁ , Michael J Caruso ₁ , David V Gauvin ₁ , Jill A Dalton ₁

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引言长期以来，在毒理学研究中表征与所投予的测试物品剂量和/或暴露有关的逆境的概念一直被认为是药物安全性评估企业的一个正常方面。在药物安全性调查中完成此操作的典型方式是检查研究数据（通常侧重于临床体征，临床病理和组织病理学）以确定无可观察到的疗效水平（NOEL）和/或无可观察到的不良反应-效果级别（NOAEL）。一旦确定，这些以及其他信息可用于在人类临床试验中确定安全的起始剂量。尽管安全药理学（SP）涉及识别和表征潜在的“不良”功能效应，但NOEL（尤其是NOAEL）传统上并未在SP研究的解释和报告中应用。方法进行了一项合同研究实验室总时间表的匿名调查，以了解这些概念在GLP（良好实验室规范）的心血管，呼吸和神经行为安全性研究中的最新应用。结果研究样本（N = 635）的结果总体上确认了适当剂量选择策略的应用，因为观察到的严重不良事件（事前观察最终与发病/死亡相关）的比例非常低（<1％）。数据进一步表明或者没有提及NOEL / NOAEL（50％），或者明确地标识了NOEL / NOAEL（28％）或NOAEL（21％）。在大多数情况下，确定NOAEL的情况与最高剂量同时出现（例如，可能有与药物相关的发现，但是在剂量范围内，这些药物被视为非不良药物）。讨论尽管逆境的概念肯定与非临床SP研究相关，但实际的实际做法似乎反映了一个历史，该历史通常避免了以毒理学为导向的分类，例如NOAEL。关于NOAELs在安全性药理学研究中的适用性仍然存在疑问，重要的是，在特定情况下可以考虑将这种逆境指认为在早期人类临床试验中增加对相对风险和缓解风险的理解的价值。

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NOEL and NOAEL: A retrospective analysis of mention in a sample of recently conducted safety pharmacology studies.

INTRODUCTION The concept of characterizing adversity in relation to administered test article dose and/or exposure within toxicology studies has long been considered a normal aspect of the drug safety evaluation enterprise. The typical way this is done in drug safety investigations is by examining study data, often with focus on clinical signs, clinical pathology and histopathology, to determine a No-Observable-Effect-Level (NOEL) and/or a No-Observable-Adverse-Effect-Level (NOAEL). Once established, these, with other information, may be used to identify a safe starting dose in human clinical trials. Although safety pharmacology (SP) is concerned to identify and characterize potentially "adverse" functional effects, NOEL, and particularly NOAEL, traditionally do not have application in SP study interpretation and reporting. METHODS An anonymized survey of a contract research laboratory master schedule was undertaken to appreciate recent usage of these concepts in GLP (Good Laboratory Practice) cardiovascular, respiratory, and neurobehavioral safety studies. RESULTS Results across the sample of studies (N = 635) generally confirmed application of appropriate dose selection strategies, as there was a very low proportion (<1%) of observed severe adverse events (antecedent observations ultimately associated with morbidity/mortality). Data further indicated either no mention of NOEL/NOAEL (50%), or alternately, explicit identification of NOEL (28%), or NOAEL (21%). The majority of times a NOAEL was identified, it was also the case that this coincided with the highest dose administered (e.g., there may have been drug-related findings, but these were considered non-adverse across the dose range). DISCUSSION While the concept of adversity is certainly relevant to nonclinical SP studies, actual current practices appear to reflect a history which generally avoids toxicologically-oriented classifications such as NOAEL. Questions remain regarding the applicability of NOAELs to safety pharmacology studies, including, importantly, the specific circumstances under which such designations of adversity may be considered to add value to understandings of relative risk and risk mitigation in early human clinical trials.

更新日期：2019-11-01

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