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

描述：(申请人描述) 对于提议的工作，我们的意图是作为北美大脑的一部分 肿瘤联盟(NABTC)将获得选定药物的药理信息 治疗中枢神经系统I/II期临床试验中的抗癌药物 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，加州大学旧金山分校医学博士-负责人)确定 机构)。对于药物动力学研究，这项工作将由两个部分组成 阶段：(A)制定或实施适当的分析性文件 用于测量可能的组织和生物体液的方法。 具体来说，将建立高效液相或气相色谱方法进行定量 正在研究的化合物(如紫杉醇和替莫唑胺)。发展 适当的方法学可能需要测定物理化学 性质，如溶解度，药物与血浆蛋白的结合和 不同温度下药物在不同基质中的稳定性。这 阶段必须顺利完成，才能进入下一个阶段 相位。(B)该药的药代动力学/药效学特征 正在进行临床评估的药物将包括：最大血药浓度或脑脊液 浓度；血浆或脑脊液清除量； 稳态；血浆(CSF)时间曲线下面积；组织或脑脊液 分布和谐波平均血浆/脑脊液半衰期。我们会尝试 将这些药代动力学参数与观察到的生物 影响，如毒性和/或反应数据。一般来说，这些研究将 被限制在母体药物中。但是，在广泛使用 新陈代谢的发生，用于测量的分析方法的发展 代谢物的比例将被追踪，这样平行的 这些化合物的药代动力学/药效学测定可以是 与母体化合物一起进行。

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.