Dean J H
Sanofi Research Division, Sanofi Pharmaceuticals, Inc., Malvern, PA 19355, USA.
Toxicology. 1997 Apr 11;119(1):95-101. doi: 10.1016/s0300-483x(96)03601-3.
Unfortunately, the principal routine toxicology methods employed for the safety assessment of new products are over 40 years old and rely primarily on histopathological evaluation. It is difficult to introduce newer immunotoxicology or molecular toxicology methods into toxicity assessment without extensive and time consuming validation requiring several years due to concern for standardization of methods, inter-laboratory replication of these methods and resistance to acceptance of new methods by both regulatory agencies and industry. During the past 15 years, significant progress has occurred in the fields of molecular biology and basic/clinical immunology which promoted the establishment of newer more sensitive methods to assess cell injury or immune system effects in humans and laboratory animals. This brings us to the challenges associated with trying to introduce new immunotoxicology or molecular toxicology methods into the safety assessment of new products. Our experience at Sanofi Research with immunotoxicity methods development or validation and approaches for molecular toxicology and their application to the preclinical development of new chemical drug entities (NCE) will be discussed. Laboratories to investigate immunotoxicity and molecular toxicology were established during the past 10 years among several industrial research groups for the evaluation of new chemicals and drug candidates. Immunotoxicology methods have been selected and optimized for rodent testing leading to four inter-laboratory collaborative studies to demonstrate the reproducibility and value of these methods for predicting toxicity. Our experience at Sanofi has led us to believe that these newer methods can represent an important part of drug development, should be applied on an as needed basis, and should be driven by data suggestive of an immune or molecular toxicology effect or by the class of the chemical being evaluated. Ex vivo and in vitro assays are selected from a menu of validated methods for application on a case-by-case basis. Results in this area with inter-laboratory validation of these methods will be discussed. Newer molecular toxicology and immunotoxicity methods are beginning to play a more important role in the safety evaluation and risk assessment process.
不幸的是，用于新产品安全性评估的主要常规毒理学方法已有40多年历史，且主要依赖组织病理学评估。由于担心方法的标准化、这些方法在不同实验室间的可重复性以及监管机构和行业对新方法的接受度问题，在没有耗时数年的广泛验证的情况下，很难将更新的免疫毒理学或分子毒理学方法引入毒性评估。在过去15年里，分子生物学和基础/临床免疫学领域取得了重大进展，这推动了更新、更灵敏的方法的建立，以评估人类和实验动物的细胞损伤或免疫系统效应。这给我们带来了在新产品安全性评估中引入新的免疫毒理学或分子毒理学方法所面临的挑战。将讨论赛诺菲研究所在免疫毒性方法开发或验证以及分子毒理学方法及其在新化学药物实体（NCE）临床前开发中的应用方面的经验。在过去10年中，几个工业研究小组建立了研究免疫毒性和分子毒理学的实验室，用于评估新化学品和候选药物。已选择并优化了用于啮齿动物测试的免疫毒理学方法，进行了四项实验室间合作研究，以证明这些方法在预测毒性方面的可重复性和价值。赛诺菲的经验使我们相信，这些更新的方法可以成为药物开发的重要组成部分，应根据需要应用，并应由表明免疫或分子毒理学效应的数据或所评估化学品的类别驱动。根据具体情况从一系列经过验证的方法中选择体外和体内试验。将讨论该领域这些方法的实验室间验证结果。更新的分子毒理学和免疫毒性方法开始在安全性评估和风险评估过程中发挥更重要的作用。
