PHARMACOKINETIC/PHARMACODYNAMICS OF CNS THERAPY

CNS 治疗的药代动力学/药效动力学

• 批准号: 2103647
• 负责人: JOHN G KUHN
• 金额: $ 9.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-28 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103647
• 关键词: analytical method; body fluids; central nervous system neoplasms; cerebrospinal fluid; clearance rate; excretion; gas chromatography; high performance liquid chromatography; human tissue; method development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; oral administration; pharmacokinetics

For the proposed work, it is our intent to derive pharmacological information on selected anticancer agents in phase I/II clinical evaluation for the treatment of CNS malignancies. The drugs to be studied and the extent of each study will be determined by the Program Director (Michael Prados, M.D.). It will be one of the prime goals for participants in the pharmacology core facility to interact with the other investigators on this project. Such interactions will help us to relate our pharmacokinetic findings to the biological effects and to the mechanisms of action at the CNS level. For a complete pharmacological study, the work will consist of two phase: (a) Development or implementation of a suitable analytical methodology for the measurement of likely tissue and biological fluids. Specifically, HPLC or GC methodologies will be established for quantitation of the compound (such as taxol & temozolomide) being studied. Development of appropriate methodologies may require determination of physicochemical properties such as solubilities, binding of drug to plasma proteins and stability of the drugs in various matrixes at various temperatures. This phase must be successfully completed before entering into the next phase. (b) Characterization of the pharmacokinetics/pharmacodynamics of the agent undergoing clinical evaluation will include: maximum plasma or CSF concentration; plasma, CSF or urinary clearance; apparent volume of distribution at steady state; area under the plasma (CSF) time curve; tissue or CSF distribution; harmonic mean plasma/CSF half-lives and percent urinary excretion. Attempts will be made to correlate these pharmacokinetic parameters with the observed biological effects such as toxicity and/or response data. Generally these studies will be confined to the parent drug. However, in instances where extensive metabolism occurs, the development of analytical methodology for measurement of the metabolism occurs, the development of analytical methodology for measurement of the metabolites will be pursued so that parallel pharmacokinetic/pharmacodynamic determinations of these compounds can be conducted along with the parent compound. Limited pharmacokinetic studies may be directed at answering certain specific questions that relate to the properties of the drug being investigated. Studies of this type could involve: (a) bioavailability study to evaluate a drug for oral administration. Elucidation of the structure of metabolite(s) of the drug. This effort may include limited synthetic or Mass Spect work to establish the identify of the unknown drug (c) study of the plasma and CSF pharmacokinetics in nonhuman primates.

对于拟议的工作，我们的目的是获得药理 I/II期临床中选定的抗癌药物的信息 评估中枢神经系统恶性肿瘤的治疗。 药物是 研究和每个研究的范围将由程序确定 导演（Michael Prados，医学博士）。 这将是 药理学核心设施的参与者与他人互动 该项目的调查人员。 这样的互动将帮助我们建立联系 我们对生物学作用的药代动力学发现和 CNS级别的作用机理。 完整的药理 研究，工作将包括两个阶段：（a）开发或 实施适当的分析方法进行测量 可能的组织和生物流体。 具体而言，HPLC或GC 将建立方法来定量化合物（这样 作为紫杉醇和替莫唑胺的研究。 适当的发展 方法可能需要确定理化特性 例如溶解度，药物与血浆蛋白的结合和稳定性 在各种温度下的各种基质中的药物。 这个阶段 必须在进入下一阶段之前成功完成。 （b） 药代动力学/药效学的表征 接受临床评估将包括：最大血浆或CSF 专注;等离子体，CSF或泌尿率清除；明显的体积 稳态分布；等离子体（CSF）时间曲线下的面积； 组织或CSF分布；谐波平均等离子体/CSF的半衰期和 尿液排泄百分比。 尝试将这些尝试关联 具有观察到的生物学作用的药代动力学参数，例如 毒性和/或响应数据。 通常，这些研究将被限制 给家长药物。 但是，在广泛代谢的情况下 发生的是，开发分析方法来测量 发生新陈代谢，开发分析方法论 将追求代谢物的测量 这些化合物的药代动力学/药效学测定可以是 与父院一起进行。 有限的药代动力学 研究可能是针对回答某些特定问题的 与正在研究的药物的特性有关。 研究 类型可能涉及：（a）生物利用度研究以评估口服药物 行政。 阐明代谢物的结构 药品。 这项工作可能包括有限的合成或质量SPECT工作 确定血浆和血浆研究未知药物的识别 非人类灵长类动物中的CSF药代动力学。