Sasseville V G, Lane J H, Kadambi V J, Bouchard P, Lee F W, Balani S K, Miwa G T, Smith P F, Alden C L
Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., 45 Sidney Street, Cambridge, MA 02139, USA.
Chem Biol Interact. 2004 Nov 1;150(1):9-25. doi: 10.1016/j.cbi.2004.06.009.
The financial investment grows exponentially as a new chemical entity advances through each stage of discovery and development. The opportunity exists for the modern toxicologist to significantly impact expenditures by the early prediction of potential toxicity/side effect barriers to development by aggressive evaluation of development-limiting liabilities early in drug discovery. Improved efficiency in pharmaceutical research and development lies both in leveraging "best in class" technology and integration with pharmacologic activities during hit-to-lead and early lead optimization stages. To meet this challenge, a discovery assay by stage (DABS) paradigm should be adopted. The DABS clearly delineates to discovery project teams the timing and type of assay required for advancement of compounds to each subsequent level of discovery and development. An integrative core pathology function unifying Drug Safety Evaluation, Molecular Technologies and Clinical Research groups that effectively spans all phases of drug discovery and development is encouraged to drive the DABS. The ultimate goal of such improved efficiency being the accurate prediction of toxicity and side effects that would occur in development before commitment of the large prerequisite resource. Good justification of this approach is that every reduction of development attrition by 10% results in an estimated increase in net present value by $100 million.
随着新化学实体在发现和开发的每个阶段不断推进，财务投资呈指数级增长。对于现代毒理学家来说，存在这样一个机会，即通过在药物发现早期积极评估限制开发的风险因素，对潜在毒性/副作用障碍进行早期预测，从而显著影响支出。药物研发效率的提高既在于利用“同类最佳”技术，也在于在从苗头化合物到先导化合物以及早期先导化合物优化阶段与药理活性相结合。为应对这一挑战，应采用分阶段发现检测（DABS）模式。DABS 向发现项目团队清晰地界定了将化合物推进到后续各个发现和开发阶段所需检测的时间和类型。鼓励建立一个整合核心病理学功能，将药物安全评估、分子技术和临床研究团队有效统一起来，贯穿药物发现和开发的所有阶段，以推动 DABS。提高效率的最终目标是在投入大量前期资源之前，准确预测开发过程中将会出现的毒性和副作用。这种方法的充分理由是，开发损耗每降低 10%，估计净现值将增加 1 亿美元。
