Cross Kevin P, Ponting David J
Instem 1393 Dublin Road, Columbus, OH, USA.
Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, UK.
Comput Toxicol. 2021 Nov;20. doi: 10.1016/j.comtox.2021.100186. Epub 2021 Sep 8.
The detection of -nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that -nitrosamine risk assessments be performed on all marketed medical products [EMA/351053/2019 rev 1 (2019)]. Regulation of -nitrosamine impurity levels in pharmaceutical drug substances and products is described in the ICH M7(R1) guideline where they are referred to as "cohort-of-concern" compounds as several are potent rodent carcinogens [Kroes . 2004]. EMA, U.S. FDA and other regulatory agencies have set provisional acceptable daily intake limits for nitrosamines calculated from rodent carcinogenicity TD values for experimentally measured nitrosamines or the measured TD values of close analogs. The class-specific limit can be adjusted based upon a structure activity relationship analysis (SAR) and comparison with analogs having established carcinogenicity data [EMA/369136/2020, (2020)]. To investigate whether improvements in SARs can more accurately predict -nitrosamine carcinogenic potency, an ad hoc workgroup of 23 companies and universities was established with the goals of addressing several scientific and regulatory issues including: reporting and review of -nitrosamine mutagenicity and carcinogenicity reaction mechanisms, collection and review of available, public relevant experimental data, development of structure-activity relationships consistent with mechanisms for prediction of nitrosamine carcinogenic potency categories, and improved methods for calculating acceptable intake limits for -nitrosamines based upon mechanistic analogs. Here we describe this collaboration and review our progress to date towards development of mechanistically based structure-activity relationships. We propose improving risk assessment of -nitrosamines by first establishing the dominant reaction mechanism prior to retrieving an appropriate set of close analogs for use in read-across exercises.
几种市售药品中检测到N-亚硝基二甲胺（NDMA），这使得监管机构要求对所有市售医疗产品进行亚硝胺风险评估[EMA/351053/2019修订版1（2019年）]。国际人用药品注册技术协调会（ICH）M7（R1）指南中描述了对药物原料药和产品中亚硝胺杂质水平的监管，其中几种亚硝胺被称为“关注队列”化合物，因为它们中有几种是强效啮齿动物致癌物[克罗斯等人，2004年]。欧洲药品管理局（EMA）、美国食品药品监督管理局（FDA）和其他监管机构已根据实验测量的亚硝胺的啮齿动物致癌性TD值或密切类似物的测量TD值，设定了亚硝胺的临时每日可接受摄入量限值。特定类别的限值可根据结构活性关系分析（SAR）并与具有已确定致癌性数据的类似物进行比较进行调整[EMA/369136/2020，（2020年）]。为了研究SAR的改进是否能更准确地预测亚硝胺的致癌效力，由23家公司和大学组成的一个特别工作组成立，目标是解决几个科学和监管问题，包括：亚硝胺致突变性和致癌性反应机制的报告和审查、收集和审查可用的公开相关实验数据、开发与预测亚硝胺致癌效力类别的机制一致的结构活性关系，以及改进基于机制类似物计算亚硝胺可接受摄入量限值的方法。在此，我们描述这种合作，并回顾我们迄今为止在基于机制的结构活性关系开发方面取得的进展。我们建议通过首先确定主要反应机制，然后检索一组合适的密切类似物用于类推法练习，来改进亚硝胺的风险评估。
