PRECLINICAL PHARMACOLOGICAL STUDIES

合理的药物开发战略的一个重要组成部分是 研究药物的毒性与疗效的相关性 它们在动物体内的血浆和组织浓度。一位成功的 这一方法的结果在很大程度上取决于敏感药物的可用性。 生物基质中化合物的定量方法及注意事项 临床前药理学和毒理学研究的整合。这 合同为进行定义的工作提供持续的资源 正在考虑的抗肿瘤和抗艾滋病毒药物的药理学研究 由发育治疗学项目提供。分析方法有 用来定量血浆、尿液和其他生物液体中的化合物， 和组织处于与预期的治疗和/或 从体外和体内评估确定的毒性范围。电浆 稳定性和蛋白质结合研究在早期阶段进行 复合型发展。然后，测试化合物的药代动力学 在下列啮齿动物、狗和非人灵长类动物中进行评估 按不同路线和时刻表管理，特别是那些计划的 用于临床试验。对于某些化合物，特别是抗艾滋病毒 药物，口服(或其他非注射用)生物利用度的测定是 强调。为新药的人体药理提供更好的预测 药物在临床试验之前，比较代谢研究是 使用动物和人类肝脏对选定的化合物进行研究 准备工作。通过这份合同获得的数据也有助于 药物引导剂量递增策略在临床中的应用 I期临床试验。

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.