Preclinical Pharmacological Studies of Antitumor & Other Therapeutic Agents

本合同提供了一种资源，用于利用NCI开发治疗计划选择用于临床前开发的药物进行以下类型的研究：(1)开发分析方法，以在与预期治疗和/或毒性范围相对应的水平上量化血浆、尿液和其他生物基质中的化合物；(2)血浆稳定性和蛋白质结合研究，在化合物开发的早期阶段进行，以确保适当的样品处理并帮助解释动物研究；(3)通过各种途径和时间表给药后的药代动力学特征，包括适当时确定口服生物利用度；(4)对体内和体外各种系统(如S9组分、微粒体、肝细胞、P450亚型、肝脏切片)中产生的药物代谢物进行量化和鉴定；以及(5)评估在肿瘤或替代组织中的药效学效应，以及这些效应与药物水平和/或总药物暴露的相关性。预计从详细的药代动力学研究中获得的数据将有助于设计临床前疗效和毒理学研究以及选定药物的I期临床试验。承包商提交的技术报告将包括在NCI或其他机构提交给FDA的IND中。 根据本合同选择进行研究的化合物可能来自各种同行评审的外部来源，例如Canter治疗药物开发集团(DDG)的部门，用于NCI持有的潜在研究新药(IND)应用，以及快速获得干预开发(RAID)和快速获取NCI发现资源(R*A*N*D)计划，用于研究人员持有的IND。此外，NCI的临床显像剂和增强剂开发(DCide)计划、NIDDK 1型糖尿病RAID计划和NIH路线图RAID计划(为许多治疗类别的候选药物的开发提供支持)也产生了其他开发项目。NCI的内部计划也是用于研究的抗癌化合物的来源。

This contract provides a resource for conducting the following types of studies with agents selected for preclinical development by the Developmental Therapeutics Program, NCI: (1) development of analytical methods to quantify compounds in plasma, urine, and other biological matrices at levels corresponding to the expected therapeutic and/or toxic range; (2) plasma stability and protein binding studies, which are conducted at an early stage of compound development to ensure proper sample handling and to aid in the interpretation of animal studies; (3) pharmacokinetic characterization following administration to animals by various routes and schedules, including a determination of oral bioavailability where appropriate; (4) quantification and identification of drug metabolites generated in vivo and in various in vitro systems (e.g., S9 fractions, microsomes, hepatocytes, P450 isoforms, liver slices); and (5) assessment of pharmacodynamic effects in tumor or surrogate tissues and correlation of these effects with drug levels and/or total drug exposures. It is anticipated that the data obtained from detailed pharmacokinetic investigations will be useful in the design of preclinical efficacy and toxicology studies and Phase I clinical trials of selected agents. Technical reports submitted by the contractors will be included in INDs submitted to the FDA by the NCI or other institutions. Compounds selected for study under this contract may arise from a variety of peer-reviewed extramural sources such as the Division of Canter Treatment Drug Development Group (DDG) for potential NCI-held Investigational New Drug (IND) applications and the Rapid Access to Intervention Development (RAID) and Rapid Access to NCI Discovery Resources (R*A*N*D) Programs for investigator-held INDs. In addition, development projects also arise from other pipelines such as the NCI Development of Clinical Imaging Agents and Enhancers (DCIDE) program, the NIDDK Type-1 Diabetes RAID program, and the NIH Roadmap RAID Program (which provides support for development of candidate agents in many therapeutic categories). The NCI intramural program has also been a source of anticancer compounds for study.