CORE--PHARMACOKINETICS/PHARMACODYNAMICS

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The overall goal of Core D is to provide the Program Project with a preclinical pharmacology program for the protease inhibitors that are identified in Project 1 and Core B, and tested in Projects 2 and 3. This will be accomplished by defining the disposition processes responsible for elimination of the protease inhibitors, by characterizing the pharmacokinetics of protease inhibitors in animal models, and by developing pharmacokinetic/pharmacodynamic correlations with respect to both measures of efficacy and toxicity. Specific aims in Core D are: 1) determine the processes responsible for the inactivation of protease inhibitors identified in Core B and the novel inhibitors designed and synthesized in Project 1; test the hypothesis that small molecule protease inhibitors are likely to be substrates for CYP3A and p-glycoprotein; 2) quantitate the presence (or confirm the absence) of potential "inactivators" of the developed protease inhibitors within the in vitro cell biological assays and animal tumor models used in Core C and Projects 2 and 3; 3) test promising protease inhibitors (on the basis of Project 2 studies) in preclinical animal models using pharmacokinetic and pharmacodynamic methods; 4) Utilizing sparse data sampling analysis techniques, define the pharmacokinetics of the promising protease inhibitors in animal models. 5) Use population analysis methods with concentration-efficacy/toxicity measurements to develop pharmacokinetic/pharmacodynamic models for the promising protease inhibitors (using measurements obtained in Project 2 and those from this Core). In this way Core D serves our overall Program Project application by evaluating and optimizing the in vivo preclinical studies of Projects 2 and 3, and Core C required to assess the efficacy and/or toxicity of the protease inhibitors identified in Core B and/or designed and synthesized in Project 1.