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

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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.