PRECLINICAL PHARMACOLOGICAL STUDIES OF ANTITUMOR AND ANT

抗肿瘤和ANT的临床前药理学研究

• 批准号: 6209004
• 负责人: KENNETH K CHAN
• 金额: $ 15.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6209004
• 关键词: Primates; Rodentias; animal tissue; antiAIDS agent; antineoplastics; chemical stability; cytochrome P450; dogs; drug administration routes; drug metabolism; drug screening /evaluation; human tissue; injection /infusion; intraperitoneal injections; intravenous administration; method development; oral administration; pharmacokinetics; protein binding; protein isoforms

This contract provides a resource for preclinical pharmacology investigations of antitumor and anti-HIV agents under development by the Division of Cancer Treatment and Diagnosis, NCI. Defined pharmacological studies are assigned to the contractor through a Work Assignment system. These studies may include (1) development and validation of sensitive analytical methodology for quantitation of compounds in biological fluids and tissues; (2) in vitro stability and protein binding studies; (3) comparative in vitro metabolism studies using animal and human tissue preparations and expressed CYP450 isoforms; (4) determination of pharmacokinetic profiles and derived parameters following intravenous, intraperitoneal, subcutaneous (bolus and/or infusion) and oral dosing in rodents, dogs, and non-human primates; and (5) identification and pharmacokinetic analysis of drug metabolites. Data obtained in these studies are used to determine the most appropriate route, dose, and schedule of administration for achieving sustained therapeutic concentrations of an agent in biological fluids. For some compounds, particularly cytostatic antitumor or anti-HIV agents (which may be administered to patients for long periods of time), determination of oral bioavailability is emphasized. Preclinical pharmacology studies are generally performed in parallel with (and are designed to aid in the interpretation of) preclinical toxicology evaluations. Together, these investigations provide necessary data for IND filing as well as a rational basis for the clinical Phase I starting dose and dose escalation scheme.

该合同为 NCI 癌症治疗和诊断部门正在开发的抗肿瘤和抗 HIV 药物的临床前药理学研究提供了资源。定义的药理学研究通过工作分配系统分配给承包商。 这些研究可能包括（1）开发和验证生物体液和组织中化合物定量的灵敏分析方法； (2)体外稳定性和蛋白结合研究； (3) 使用动物和人体组织制剂和表达的 CYP450 亚型进行比较体外代谢研究； (4) 确定啮齿动物、狗和非人灵长类动物静脉内、腹膜内、皮下（推注和/或输注）和口服给药后的药代动力学特征和衍生参数； (5)药物代谢物的鉴定及药代动力学分析。这些研究中获得的数据用于确定最合适的给药途径、剂量和时间表，以实现生物液体中药剂的持续治疗浓度。对于某些化合物，特别是细胞抑制性抗肿瘤药物或抗 HIV 药物（可以长期给予患者），强调口服生物利用度的测定。临床前药理学研究通常与临床前毒理学评估并行进行（旨在帮助解释）。总之，这些研究为 IND 申报提供了必要的数据，并为临床 I 期起始剂量和剂量递增方案提供了合理的基础。