PHARMACOKINETIC/PHARMACODYNAMICS OF CNS THERAPY

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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.