PHASE I/II PK/PD STUDIES OF AGENTS FOR CNS MALIGNANCIES

描述：（申请人的描述） 对于拟议的工作，这是我们的意图，作为北美大脑的一部分， 肿瘤联盟（NABTC），以获得选定药物的药理学信息 用于治疗CNS的I/II期临床试验中的抗癌药 恶性肿瘤。 将研究的药物和每项研究的范围 由项目负责人（Michael Prados，M.D. UCSF-铅 机构）。 对于药代动力学研究，工作将包括两项 （a）制定或执行适当的分析性战略， 用于测量可能的组织和生物流体的方法。 具体而言，将建立用于定量的HPLC或GC方法 化合物（如紫杉醇和替莫唑胺）的研究。 发展 适当的方法可能需要测定 性质如溶解度、药物与血浆蛋白的结合， 药物在各种基质中在各种温度下的稳定性。 这 必须在进入下一阶段之前成功完成B e 相位 (b)药物的药代动力学/药效学表征 正在进行临床评价的药物将包括：最大血浆或CSF 浓度;血浆或CSF清除率;表观分布容积 稳态;血浆（CSF）时间曲线下面积;组织或CSF 分布和调和平均血浆/CSF半衰期。 将尝试 为了将这些药代动力学参数与观察到的生物学参数相关联， 影响，如毒性和/或反应数据。 这些研究一般将 仅限于母体药物。 然而，在广泛 代谢发生时，测量分析方法的发展 的代谢产物将被追求， 这些化合物的药代动力学/药效学测定可 与母体化合物一起沿着进行。

DESCRIPTION: (Applicant's Description) For the proposed work, it is our intent as part of the North American Brain Tumor Consortium (NABTC) to derive pharmacological information on selected anticancer agents in Phase I/II clinical trials for the treatment of CNS malignancies. The drugs to be studied and the extent of each study will be determined by the Program Leader (Michael Prados, M.D. UCSF-Lead Institution). For a pharmacokinetic study, the work will consist of two phases: (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 b e f o r e entering into the next phase. (b) Characterization of the pharmacokinetics/pharmacodynamics of the agent under going clinical evaluation will include: maximum plasma or CSF concentration; plasma or CSF clearance; apparent volume of distribution at steady state; area under the plasma (CSF) time curve; tissue or CSF distribution and harmonic mean plasma/CSF half-lives. 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 metabolites will be pursued so that parallel pharmacokinetic/pharmacodynamic determinations of these compounds can be conducted along with the parent compound.