PRECLINICAL TOXICLOGY/PHARMACOLOGY/DEVELOP DRUGS/AIDS

临床前毒理学/药理学/开发药物/艾滋病

• 批准号: 3616684
• 负责人: JOHN G PAGE
• 金额: $ 41.39万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-04 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3616684
• 关键词: Rodentias; antiAIDS agent; bioassay; blood brain barrier; dogs; dosage; drug adverse effect; drug metabolism; drug tolerance; pharmacokinetics

The objective of these contracts is to acquire for the direct benefit of the Government, pharmacologic and toxicologic data on new drugs for the treatment of the Acquired Immunodeficiency Syndrome. The data will serve as the basis of the Government's filing for an INDA to institute human clinical trials. This data is collected in a series of toxicology and pharmacology studies and consists of the following: Analytical Phase: Drug identity analysis (e.g., IR, NMR, MP, MS, etc.), validation of the procedures supplied by the NCI for dose concentration analyses and validation of the requisite methodology for assay of drug in biological fluids. Pharmacokinetic Phase: Plasma elimination kinetics will be determined in dogs and possibly in rodents after single intravenous and oral doses of drug. Oral bioavailability and plasma clearance rates will be determined in order to establish the dose required to produce the minimum viral inhibitory concentration (MIC) in the plasma for future toxicity studies. It may be necessary to determine bioavailability by other routes of administration such as ip or sc. The ability of the drug to cross the blood-brain barrier will be assessed in a 72 hour continuous infusion study in dogs. Toxicity Phase: For each drug, it will be necessary to establish a maximum tolerated dose (MTD) and organ toxicity in relation to its plasma concentration in both dogs and rodents. The following types of studies may be required in this phase: Single or multiple dose studies in rodents and dogs; Continuous administration to rodents via Alzet pumps and to dogs via infusion pumps; and Twenty- eight days of repeated administration of drug to rodents and dogs.

这些合同的目的是直接收购 政府的利益，药理学和毒理学数据 治疗获得性免疫缺陷病的新药 综合症。 该数据将作为政府决策的依据 申请 INDA 进行人体临床试验。 这个数据 是在一系列毒理学和药理学研究中收集的 由以下部分组成： 分析阶段：药物身份分析（例如 IR、NMR、MP、MS、 等），验证 NCI 提供的剂量程序 浓度分析和必要方法的验证 用于测定生物体液中的药物。 药代动力学阶段：血浆消除动力学将是 在狗和可能的啮齿动物中进行单次静脉注射后测定 和口服药物剂量。 口服生物利用度和血浆清除率 将确定速率以确定所需的剂量 产生最低病毒抑制浓度（MIC） 血浆用于未来的毒性研究。 可能有必要 通过其他给药途径确定生物利用度，例如 作为 ip 或 sc。 药物穿过血脑的能力 将在 72 小时连续输注研究中评估屏障 狗。 毒性阶段：对于每种药物，有必要确定 最大耐受剂量（MTD）和与相关的器官毒性 其在狗和啮齿动物中的血浆浓度。 下列 此阶段可能需要研究类型： 单一或多项 啮齿动物和狗的剂量研究；持续给药以 啮齿动物通过 Alzet 泵，狗通过输液泵；和二十—— 对啮齿动物和狗重复给药八天。