PRECLINICAL PHARMACOLOGICAL STUDIES OF ANTITUMOR AND ANT

该合同为NCI癌症治疗和诊断部正在开发的抗肿瘤和抗艾滋病毒药物的临床前药理学研究提供了资源。规定的药理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)开发和验证用于定量生物液和组织中化合物的灵敏分析方法；(2)体外稳定性和蛋白质结合研究；(3)使用动物和人体组织制剂进行的体外代谢比较研究；(4)在啮齿动物、狗和非人灵长类动物体内静脉、腹膜、皮下(团注和/或输注)和口服给药后的药代动力学特征和衍生参数的测定；(5)药物代谢物的鉴定和药代动力学分析。在这些研究中获得的数据被用来确定最合适的给药路线、剂量和给药程序，以实现生物液中药物的持续治疗浓度。对于一些化合物，特别是细胞抑制抗肿瘤或抗艾滋病毒药物(可能长期给患者服用)，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(并旨在帮助解释)。总之，这些研究为IND申报提供了必要的数据，也为临床I期起始剂量和剂量递增计划提供了合理的基础。

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.