Preclinical / Clinical Pharmacodynamic Evaluation

项目2摘要 FAME应用的首要目标是开发整合酶抑制剂MK-1的薄膜配方。 2048在一周内在宫颈和阴道组织中达到可测量的药物水平 申请。项目2的广泛的、长期的目标是在 非人灵长类(核心B)和临床研究(项目3)正在以一种将建立MK-2048的方式 以持续的方式提供，以防止艾滋病毒在体外生殖器组织中的感染，这是 产品功效。第二个广泛的目标是表征转运蛋白的表达和活性以及 生殖器组织中的代谢酶可能会影响组织中可利用的MK-2048的水平。 Core C将利用这项工作来开发定义良好的PD/PK模型，以估计 需要在组织中传递和保留，以保护免受艾滋病毒感染。定义PD/PK联系是一个 药品开发的基本组成部分。我们的实验室率先使用了粘膜组织 用于评估药物制剂的安全性和有效性以及体外激发试验的发展 (在使用产品后从试验参与者身上提取粘膜组织，并在实验室挑战艾滋病毒)用于宫颈 与阴道黏膜组织定义PD/PK相关。我们还致力于优化样本收集 和测试。利用我们的经验，我们将评估外植体粘膜化验、腔液、 和体外组织，以提供人类和非人类灵长类动物的药效学评估。我们的 具体目标是1)描述体外培养的药效学/药代动力学关系， 2)测定药物转运体和代谢酶在体外和体外对MK-2048活性的影响 活体模型，以及3)定义多室药效学活性。解决这些目标将使我们能够 准确估计预防艾滋病毒(SIV)感染所需的MK-2048的数量，如果卢米诺和 药物的组织水平与这种保护作用密切相关。这项工作的高潮将是提供一个新的 持久剂型。

PROJECT 2 ABSTRACT The overarching goal of the FAME application is to develop a film formulation of the integrase inhibitor MK- 2048 that achieves measurable drug levels in the cervical and vaginal tissues over one week following a single application. The broad, long term goal of Project 2 is to provide pharmacodynamic assessments in the nonhuman primate (Core B) and clinical studies (Project 3) in a manner that will establish MK-2048 is being delivered in a sustained manner to prevent HIV infection in the genital tissues ex vivo, a key determinant of product efficacy. A second broad term goal is to characterize the expression and activity of the transporter and metabolizing enzymes in the genital tissues which could impact the levels of MK-2048 available in the tissues. This work will be utilized by Core C to develop well defined PD/PK models to estimate the amount of drug that needs to be delivered and retained in the tissue for protection against HIV. Defining PD/PK linkages is a fundamental component of drug product development. Our laboratory has pioneered the use of mucosal tissue for evaluating drug formulation for safety and efficacy and the development of the ex-vivo challenge assay (taking mucosal tissue from trial participants after product use and challenging with HIV in the lab) for cervical and vaginal mucosal tissue to define PD/PK correlates. We have also worked to optimize sample collection and testing. Leveraging our experience, we will evaluate drug activity in explant mucosal assays, luminal fluid, and ex vivo tissue to provide pharmacodynamic assessments across humans and nonhuman primates. Our specific aims are 1) Characterize pharmacodynamic / pharmacokinetic relationships in ex vivo explant cultures, 2) Determine the role of drug transporters and metabolizing enzymes on MK-2048 activity in in vitro and ex vivo models, and 3) Define multi-compartment pharmacodynamic activity. Addressing these aims will allow us to accurately estimate the amount of MK-2048 required to prevent HIV (SHIV) infection and if luminal and tissue levels of drug coinside with this protection. The culmination of this work will be to provide a new sustained dosage form.