Pharmacokinetic Studies with Selected Anticancer Compounds in NSG Mice

选定的抗癌化合物在 NSG 小鼠中的药代动力学研究

• 批准号: 10282058
• 负责人: JAN BEUMER
• 金额: $ 6.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282058
• 关键词: Biological Assay; Biological Availability; Blood specimen; Collection; Contractor; Data; Data Analyses; Dose; Drug Kinetics; Exercise; Measures; Minor; Modeling; Mus; Performance; Pharmaceutical Preparations; Plasma; Procedures; Protocols documentation; Route; Sampling; Schedule; Specific qualifier value; Time; Validation; Vendor; anti-cancer; base; cost; novel; small molecule

The purpose of this Task Order is to characterize the plasma pharmacokinetics (PK) of small molecule anticancer compounds in mice as outlined below. Rapid turn-around is required. There is a base period and options under this task order. For the base period: 1. Use a standard LC-MS/MS bioanalytical approach for quantification of a small drug-like molecule in mouse plasma. A “generic” assay platform is acceptable and validation to full FDA bioanalytical guidance is not required. An internal standard will be identified and used as a measure of acceptable assay performance. An LLOQ of <10 ng/mL is desirable. 2. It is anticipated that most, if not all, studies will be performed using NSG mice. The NCI will supply the mice for each study to the extent possible, but please include plans for acquisition from an outside vendor should the need arise. 3. Carry out the appended protocol for a mouse PK study with compound(s) that will be provided by the NCI. The protocol specifies 2 (likely unrelated) compounds, 1 route of administration, 8 collection time points for each route, and 3 mice/time point, for a total of 48 plasma samples to be generated for analysis. Appropriate blanks, standards, and QC samples should be included. Novel blood sampling procedures, including micro-bleeds, may be proposed by the offeror. 4. Pharmacokinetic data analysis should include standard non-compartmental modeling to determine Cmax (po), C0 (iv), Tmax, AUC0∞, AUClast, CL, and t½, Vss (or Vd), and %F for each compound to the extent permitted by the data obtained. For Options 1 - 9: 1. For each Option the contractor shall perform PK/bioavailability studies as outlined under “Base Period” for one or two additional compounds per Option. Minor adjustments to the protocol that should not affect cost or schedule (e.g., routes of administration, specific sampling times) may be made. For example, a single route of administration may be used to evaluate two compounds or one compound may be evaluated using two dose levels. Options may be exercised at any time within the Task Order period of performance

本任务顺序的目的是表征小分子抗癌化合物在小鼠体内的血浆药代动力学 (PK)，如下所述。需要快速周转。该任务订单下有一个基准期和选项。 对于基期： 1. 使用标准 LC-MS/MS 生物分析方法对小鼠血浆中的小药物样分子进行定量。 “通用”检测平台是可以接受的，并且不需要对完整的 FDA 生物分析指南进行验证。 将确定内部标准并将其用作可接受的分析性能的衡量标准。 LLOQ <10 ng/mL 是理想的。 2. 预计大多数（如果不是全部）研究将使用 NSG 小鼠进行。 NCI 将尽可能为每项研究提供小鼠，但请包括在需要时从外部供应商采购的计划。 3. 使用 NCI 提供的化合物进行小鼠 PK 研究的附加方案。 该方案指定了 2 种（可能不相关）化合物、1 种给药途径、每种途径 8 个收集时间点以及 3 只小鼠/时间点，总共生成 48 个血浆样本用于分析。应包括适当的空白、标准品和 QC 样品。投标人可能会提出新颖的血液采样程序，包括微出血。 4. 药代动力学数据分析应包括标准的非房室模型，以确定每种化合物在获得的数据允许的范围内的 Cmax (po)、C0 (iv)、Tmax、AUC0∞、AUClast、CL 和 t½、Vss（或 Vd）和 %F。 对于选项 1 - 9： 1. 对于每个选项，承包商应按照“基准期”中的概述，针对每个选项的一种或两种附加化合物进行 PK/生物利用度研究。可以对方案进行不影响成本或时间表（例如给药途径、具体采样时间）的微小调整。 例如，可以使用单一施用途径来评估两种化合物，或者可以使用两种剂量水平来评估一种化合物。 期权可在任务订单履行期内随时行使