Preclinical Pharmacological Studies of Antitumor & Other Therapeutic Agents

抗肿瘤的临床前药理研究

• 批准号: 8008916
• 负责人: MERRILL J EGORIN
• 金额: $ 88.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2010-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008916
• 关键词: Animals; Area Under Curve; Autopsy; Biochemical; Biological; Biological Assay; Biological Availability; Biological Models; Body Fluids; Canis familiaris; Categories; Clinical; Computing Methodologies; Continuous Infusion; Contractor; Contracts; Cytochrome P450; Data; Development; Developmental Therapeutics Program; Dose; Drug Exposure; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Enhancers; Ensure; Enzymes; Extramural Activities; Genomics; Half-Life; Hepatocyte; Human; Image; In Vitro; Institution; Insulin-Dependent Diabetes Mellitus; Intramural Research Program; Intravenous; Investigation; Investigational New Drug Application; Laboratories; Liquid substance; Liver; Maintenance; Measurement; Membrane; Methodology; Microsomes; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Oral; Pathway interactions; Peer Review; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Plasma; Plasma Proteins; Process; Protein Binding; Protein Isoforms; Proteomics; Rapid Access to Intervention Development; Rattus; Research Design; Research Personnel; Resources; Route; Sampling; Schedule; Shipping; Ships; Slice; Solubility; Solvents; Source; Staging; Structure; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Toxicology; Tumor Tissue; United States National Institutes of Health; Urine; analytical method; animal tissue; cell preparation; design; drug development; in vivo; intraperitoneal; metabolic abnormality assessment; nonhuman primate; pharmacokinetic model; pre-clinical; preclinical efficacy; programs; subcutaneous; technical report; tumor; urinary

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.

该合同为NCI开发治疗学计划选择用于临床前开发的药物进行以下类型的研究提供了资源：（1）开发分析方法，以定量血浆，尿液和其他生物基质中的化合物，其水平对应于预期的治疗和/或毒性范围;（2）血浆稳定性和蛋白结合研究，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予动物后的药代动力学表征，包括在适当时测定口服生物利用度;（4）体内和各种体外系统（例如，S9组分、微粒体、肝细胞、P450亚型、肝切片）;和（5）评估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选定药物的临床前疗效和毒理学研究以及I期临床试验。承包商提交的技术报告将包含在NCI或其他机构提交给FDA的IND中。 根据本合同选择用于研究的化合物可能来自各种同行评审的校外来源，例如Canter治疗药物开发组（DDG）的潜在NCI持有的研究性新药（IND）申请以及快速访问干预开发（RAID）和快速访问NCI发现资源（R*A*N*D）计划。此外，开发项目也来自其他渠道，如NCI临床成像剂和增强剂开发（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开发提供支持）。NCI的校内项目也是抗癌化合物的研究来源。