Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
J Toxicol Sci. 2012;37(4):667-73. doi: 10.2131/jts.37.667.
The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.
药物代谢物的快速、适当的安全性评估在监管指南中有所提及，如人用药物注册技术要求国际协调会议（ICH）的指导原则，题为“非临床安全性研究指导原则用于人体临床试验和药品上市许可”（ICH M3(R2)），于 2011 年 1 月 1 日在日本实施，已成为药物开发中的一个重要问题。ICH M3(R2)第 4 步发布后，日本制药商协会（JPMA）的 63 家成员公司于 2010 年 3 月至 4 月对药物代谢物的安全性评估进行了调查。JPMA 非临床评价专家委员会的药代动力学小组进行了问卷调查，并对结果进行了汇编，以了解日本研究型制药公司目前如何评估药物代谢物的安全性。基于研究目的，“代谢物安全性测试”（MIST）的评估可以分为三个阶段：MIST 1 是评估人体药物代谢物并预测其潜在风险的阶段，MIST 2 是决定是否需要进行非临床安全性研究的阶段，MIST 3 是进行非临床安全性研究的阶段。在本文中，我们考虑当前的科学技术水平，针对每个阶段的目的，提出了典型的代谢物安全性评估方法。我们的建议是基于我们的调查结果和 2010 年 6 月日本毒理学学会第 37 届年会上关于药物代谢物安全性评估的专题讨论会得出的。
