The Pharmacology Core will provide analytical, drug metabolism and parmacokinetic services with the aim of relating drug (or appropriate metabolite) concentrations to treatment outcome. We specifically propose to support seven projects in the renewal period. As examples, we will assist in the search for a relationship between actual exposure to active metabolites of cyclophosphamide and organ toxicity (Project 5); support a comparison of marrow versus peripheral blood stem cell transplantation in patients whose busulfan levels will not be allowed to fall below 900 ng/mL, with relapse as the primary end point and the definition of a relationship between elevated busulfan levels and organ toxicity as the secondary endpoint (Projects 1 and 6); assist in the determination of a relationship between ganciclovir exposure and neutropenia in the early post-engraftment period (Project 7); and provide pharmacokinetic support to Phase I/II and Phase III trials of mofetil mycophenolate (Project 3). In some instances (e.g., Project 5); we propose to identify the causes of interpatient variability in actual exposure to active compounds at a given dose of drug in order to develop intervention strategies to minimize untoward effects and maximize desired outcome. The Pharmacology Core also will be available to address special clinical pharmacology needs that may arise in Program components in order to implement new initiatives. By establishing a central facility for planning and coordination of sampling protocols and the analytical processing of the many blood and other and other samples involved, the analytical and pharmacokinetic precision and information needed to accomplish the proposed research will be assured.
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