Gore Elizabeth R
Department of Safety Assessment, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA.
Basic Clin Pharmacol Toxicol. 2006 Apr;98(4):331-5. doi: 10.1111/j.1742-7843.2006.pto_374.x.
Routine immune function testing in preclinical drug development was established as a regulatory requirement in June of 2000 under the Committee of Proprietary Medicinal Products (CPMP) Note for Guidance on Repeated Dose Toxicity (CPMP/SWP/1042/99). The purpose of the more stringent approach to immunotoxicology testing was to better identify unintended immunosuppression; however, the requirement was met with much discussion and debate. At the center of the discussion was an attempt to reconcile opposing regulatory directives from agencies outside of Europe that adhere to a more selective, weight-of-evidence approach to functional evaluations. Uncertainty over the predictive value of the recommended immune function tests relative to conventional toxicology parameters prompted an investigation by the International Committee on Harmonization (ICH). The results of a preliminary, industry-wide survey indicated that only a low percentage of pharmaceuticals adversely affect immune function without alterations to standard toxicology parameters. Expected ICH guidelines will ultimately determine to what extent and for what purpose immune function tests will be conducted. In the meantime, optimization of the recommended immune function tests is ongoing. The T-cell dependent antibody response (TDAR) by either conventional Sheep Red Blood Cell (SRBC) plaque assay or by the modified ELISA method using either SRBC or keyhole limpet hemocyanin (KLH) as antigen is being extensively evaluated to determine best practices and procedures for preclinical immunotoxicity evaluations. This review addresses some aspects of the debate concerning the appropriateness of immune function tests for hazard identification, along with recommendations for optimizing TDAR methodology to ensure adequate sensitivity and predictability in risk assessments for immunotoxicity.
2000年6月，根据专利药品委员会（CPMP）的《重复给药毒性指导原则》（CPMP/SWP/1042/99），临床前药物开发中的常规免疫功能测试被确立为一项监管要求。对免疫毒理学测试采取更严格方法的目的是更好地识别意外的免疫抑制；然而，这一要求引发了诸多讨论和争议。讨论的核心是试图调和欧洲以外机构的相互对立的监管指令，这些机构坚持对功能评估采用更具选择性的、证据权重的方法。推荐的免疫功能测试相对于传统毒理学参数的预测价值存在不确定性，这促使国际协调委员会（ICH）进行了一项调查。一项初步的全行业调查结果表明，只有一小部分药物在不改变标准毒理学参数的情况下会对免疫功能产生不利影响。预计ICH指南最终将确定免疫功能测试在何种程度上以及出于何种目的进行。与此同时，推荐的免疫功能测试的优化工作正在进行。通过传统的绵羊红细胞（SRBC）空斑试验或使用SRBC或钥孔戚血蓝蛋白（KLH）作为抗原的改良ELISA方法进行的T细胞依赖性抗体反应（TDAR）正在得到广泛评估，以确定临床前免疫毒性评估的最佳实践和程序。本综述探讨了关于免疫功能测试用于危害识别的适当性的辩论的一些方面，以及优化TDAR方法以确保免疫毒性风险评估中有足够的敏感性和可预测性的建议。
