Phase I/I I PK/PD Studies of Agents for CNS Malignancies (NABTC PK Center)

描述（由申请人提供）：作为北美脑肿瘤联盟（NABTC, Central Operations Office）的一部分，拟成立的药代动力学中心旨在获得用于治疗中枢神经系统恶性肿瘤的I/II期临床试验中选定抗癌药物的药理学信息。要研究的药物和每项研究的范围将由小组组长（Michael Prados, m.d.， UCSF）决定。对于药代动力学研究，工作将包括四个阶段：(a)设计适当的药代动力学采样程序以纳入NABTC方案。(b)为测量可能的组织和生物液体制定或实施适当的分析方法。具体来说，将建立HPLC或LC/MS验证方法来实时定量所研究的化合物（如CCI-779和ZD1839）。(c)提供药代动力学参数，包括最大血浆或组织浓度；血浆或清除率；稳态分布的表观体积；等离子体时间曲线下面积；组织分布和谐波平均等离子体半衰期。将尝试将这些药代动力学参数与观察到的生物效应（如毒性、反应或生物替代标记物数据）联系起来。一般来说，这些研究将局限于母体药物。然而，在发生广泛代谢的情况下，将开发用于测量代谢物的分析方法，以便这些化合物的平行药代动力学/药效学测定可以与表观化合物一起进行。

DESCRIPTION (provided by applicant): For the proposed Pharmacokinetic Center, it is our intent as part of the North American Brain Tumor Consortium (NABTC, Central Operations Office) 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 Group Leader (Michael Prados, M.D., UCSF). For the pharmacokinetic studies, the work will consist of four phases: (a) Design of an appropriate pharmacokinetic sampling procedure for inclusion in the NABTC protocol. (b) Develop or implement a suitable analytical method for the measurement of likely tissue and biological fluids. Specifically, HPLC or LC/MS validated methodologies will be established for real time quantitation of the compound (such as CCI-779 & ZD1839) being studied. (c) Provision of the pharmacokinetic parameters including maximum plasma or tissue concentration; plasma or clearance; apparent volume of distribution at steady state; area under the plasma time curve; tissue distribution and harmonic mean plasma half-lives. Attempts will be made to correlate these pharmacokinetic parameters with the observed biological effects such as toxicity, response or biological surrogate marker 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 apparent compound.