CORE--PHARMACOKINETICS/PHARMACODYNAMICS

核心D的总体目标是为计划项目提供 蛋白酶抑制剂的临床前药理学计划， 在项目1和核心B中确定，并在项目2和3中测试。 这将通过定义处置过程来实现 负责消除蛋白酶抑制剂，通过表征 蛋白酶抑制剂在动物模型中的药代动力学， 与以下药物发生药代动力学/药效学相关性 关于功效和毒性的测量。 具体目标 核心D是：1）确定负责灭活的过程 核心B中鉴定的蛋白酶抑制剂和新的抑制剂 在项目1中设计和合成;测试小的假设， 分子蛋白酶抑制剂可能是CYP 3A的底物， p-糖蛋白; 2）定量存在（或确认不存在） 潜在的“灭活剂”开发的蛋白酶抑制剂内 核心C中使用的体外细胞生物学测定和动物肿瘤模型 和项目2和3; 3）测试有前途的蛋白酶抑制剂（在 项目2研究的基础）在临床前动物模型中使用 药代动力学和药效学方法; 4）利用稀疏 数据采样分析技术，定义药物的药代动力学 有前途的蛋白酶抑制剂在动物模型。 5)使用人群 浓度-疗效/毒性测量的分析方法， 开发药代动力学/药效学模型， 蛋白酶抑制剂（使用项目2中获得的测量结果， 这些核心）。 通过这种方式，核心D服务于我们的整体计划 通过评估和优化体内临床前 项目2和3以及核心C的研究，以评估其功效 和/或核心B中鉴定的蛋白酶抑制剂的毒性，和/或 在项目1中设计和合成。

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.