PRECLINICAL PHARMACOLOGICAL STUDIES

临床前药理学研究

• 批准号: 2593178
• 负责人: Donald L. Hill
• 金额: $ 9.58万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2593178
• 关键词: Primates; analytical method; antiAIDS agent; antineoplastics; clinical chemistry; dogs; drug administration rate /duration; drug administration routes; drug metabolism; drug screening /evaluation; human tissue; laboratory mouse; laboratory rat; method development; pharmacokinetics

An important component of a rational drug development strategy is the correlation of toxic and therapeutic effects of investigational agents with their plasma and tissue concentrations in animals. A successful outcome of this approach depends heavily on the availability of sensitive methods for quantitating compounds in biological matrices and the careful integration of preclinical pharmacology and toxicology studies. This 'contract provides a continuing resource for conducting defined pharmacology studies of antitumor and anti-HIV agents under consideration by the Developmental Therapeutics Program. Analytical methods are developed to quantify compounds in plasma, urine, other biological fluids, and tissues at levels corresponding to the expected therapeutic and/or toxic range as determined from in vitro and in vivo evaluations. Plasma stability and protein binding studies are conducted at an early stage of compound development. The pharmacokinetics of test compounds are then evaluated in rodents, dogs, and non-human primates following administration by various routes and schedules, especially those intended for use in clinical trials. For some compounds, particularly anti-HIV agents, determination of oral (or other non-parenteral) bioavailability is emphasized. To provide better predictions of the human pharmacology of new agents prior to clinical trial, comparative metabolism studies are conducted with selected compounds using animal and human liver preparations. Data obtained through this contract also facilitates the application of pharmacologically-guided dose escalation strategies in Phase I clinical trials.

合理的药物开发策略的一个重要组成部分是 研究药物的毒性和治疗效果的相关性 及其在动物体内的血浆和组织浓度。一个成功的 这种方法的结果在很大程度上取决于敏感信息的可用性 生物基质中化合物的定量方法和谨慎的方法 临床前药理学和毒理学研究的整合。这 '合同提供了持续的资源来进行定义的 正在考虑的抗肿瘤和抗艾滋病毒药物的药理学研究 由发育治疗计划。分析方法有 开发用于量化血浆、尿液、其他生物液体中的化合物， 和组织水平对应于预期的治疗和/或 根据体外和体内评估确定的毒性范围。等离子体 稳定性和蛋白质结合研究是在早期阶段进行的 复合式发展。然后测试化合物的药代动力学 在啮齿动物、狗和非人类灵长类动物中进行了评估 通过各种路线和时间表进行管理，特别是那些预定的路线和时间表 用于临床试验。对于某些化合物，特别是抗 HIV 化合物 药剂，口服（或其他非胃肠外）生物利用度的测定是 强调。为新药的人体药理学提供更好的预测 临床试验前的药物，比较代谢研究是 使用动物和人类肝脏使用选定的化合物进行 准备工作。 通过本合同获得的数据也有利于 药理学指导剂量递增策略的应用 I 期临床试验。