Preclinical Pharmacological Studies of Antitumor and Other Therapeutic Agents

该合同(梅奥诊所)为开展临床前药理学、药代动力学和新陈代谢研究提供资源，这些研究由发展治疗计划(NCI)选择开发的候选治疗药物进行。所选择的大多数化合物都是潜在的抗癌药物(包括那些与孤儿癌症相关的化合物)，但也有一些化合物可能是治疗一系列流行和孤儿人类疾病的药物。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，例如癌症治疗药物开发组(DDG)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内部计划是用于研究的抗癌化合物的来源。 根据合同开展的工作可能包括：(1)开发分析方法，在与预期治疗和/或毒性范围相对应的水平上对血浆、尿液和其他生物基质中的化合物进行量化；(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和帮助解释动物研究；(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。 预计从这些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。

This contract (Mayo Clinics) provides a resource for conducting preclinical pharmacology, pharmacokinetic, and metabolism studies with candidate therapeutic agents selected for development by the Developmental Therapeutics Program, NCI. Most of the compounds selected are potential anticancer agents (including those relevant to orphan cancers), but some are putative therapeutics for a wide range of prevalent and orphan human diseases. Compounds selected for study under this contract may arise from a variety of peer-reviewed extramural sources such as the Division of Cancer 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 is a source of anticancer compounds for study. Work carried out under the contract may include: (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 these 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.