目的 探讨当前新药研究中的探索性-桥接性一般毒理学研究方法及其应用价值。方法 总结当前国际同行对急性毒性试验的观点及国内外应用情况,同时详述当前国外普遍应用的用于替代急性毒性实验的最大耐受量/剂量范围寻找实验(MTD/DRF)的实验设计和优势,并结合实践经验提出在设计和实施这类研究时的关注点。结果与结论 最大耐受量/剂量范围寻找实验能为后继法规要求的新药非临床安全性评价实验的设计提供更多有价值的参考信息,是早期探索性-桥接性一般毒理学研究中较为合理和实用的研究方法。
Abstract
To discuss early exploratory bridging studies between early screening phase and pivotal general toxicology studies and their application during new drug development. METHODS The opinions on acute toxicity study from international counterparts and current application in domestic and overseas were briefly reviewed. At the same time, the study design and the strengths of an alternative maximum tolerated dose/dose range finding(MTD/DRF)study widely used abroad were fully discussed. Furthermore, considerations were also highlighted based on the authors' experience, which may aid in the design and the conduct of such bridging studies. RESULTS AND CONCLUSION MTD/DRF study could provide more valuable information for subsequent non-clinical regulatory toxicity studies. It is a rational and practical general toxicological study with bridging character.
关键词
急性毒性实验 /
最大耐受量 /
剂量范围寻找实验
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Key words
acute toxicity study /
maximum tolerated dose /
dose range finding study
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中图分类号：
R965
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参考文献
[1] CHAPMAN K, ROBINSON S. Challenging the regulatory requirement for acute toxicity studies in the development of new medicines. A workshop report. www. nc3rs. org. uk.[2] ROBINSON S, DELONGEAS J L, DONALD E, et al. A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development . Regul Toxicol Pharmacol, 2008, 50 (3):345-352.[3] ROBINSON S, CHAMAN K, HUDSON S, et al. Guidance on dose level selection for regulatory general toxicology studies for pharmaceuticals. http://www.nc3rs.org.ok/docament.aspaid=1317.[4] Concept Paper on Single Dose/Acute Toxicity. Committee for Medicinal Products for Human Use. http://www.rsugata.cin/updateguidance/emea2/2008/30241308eb.pdf.[5] SFDA.Technical Guidelines:Acute toxicity study for chemical drugs.GPT 1-1. 2005.[6] CDER, FDA. Guidance for industry:single dose acute toxicity testing for pharmaceuticals (Final).1996.[7] European Union. Single dose toxicity. European Union Medicinal Products for Human Use Guidelines (3BS1a), 1987.[8] Questions and answers on the withdrawal of the 'Note for guidance on single dose toxicity'. EMA/CHMP/SWP/81714/2010.[9] ICH M3 (R2)-Non-clinical studies for conduct of human clinical trials for pharmaceuticals.CPMP/ICH/286/95, 2009. SMITH D, COMBES R, DEPELCHIN O, et al. Optimising the design of preliminary toxicity studies for pharmaceutical safety testing in the dog .Regul Toxicol Pharmacol, 2005,41:95-101.
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脚注
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基金
国家“重大新药创制”科技重大专项课题(2012ZX09301001-006、2012ZX09302003)
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