Exploratory Pharmcokinetics of UC781 & Tenofovir Vaginal Microbicide Gel V Film

这项名为“替诺福韦和UC781的替代制剂”的中心拨款的主要目的是 开发和比较两种不同的阴道杀微生物剂配方--凝胶 以及一种薄膜，作为抗逆转录病毒药物组合物UC781和替诺福韦(TFV)的载体。这个项目，项目 4、在探索性临床研究中以直接和非侵入性的方式定量地探索PK域 对体内6个不同的隔间进行采样-体液和CD4+细胞成分均在 宫颈阴道腔、宫颈阴道组织和血液。时空药物浓度数据 收集的数据将根据药效学(PD)数据进行评估，包括疗效和毒性 中心助学金范围内的其他项目。有了这个PK-PD数据，调查人员就可以联系到 关于(1)继续开发这两种组合产品的决定，(2)可能的修改 最终的候选产品测试，以及(3)候选产品进入正式临床时的合理研究设计 测试。为了达到这些目标，我们有以下四个具体目标： 目的1.建立和验证UC781的检测方法，提高替诺福韦细胞内检测的临床敏感性 样品，并验证放射性标记与薄膜制剂的兼容性(支持Aim 3和4临床研究) 目的2.确定宫颈阴道通透性定量变化对小鼠的可行性。 分子和HIV大小的颗粒作为候选杀微生物剂毒性的衡量标准：开放标签，探索性 比较壬醇-9凝胶和通用安慰剂的临床研究。(支持具体目标3所需的)。 目的3.比较候选胶片和胶体的宫颈-阴道和全身的时空分布 UC781(Aim 3-1)和TFV(Aim 3-2)制剂的临床探索性研究 目的4.探索性人类和猕猴PK-PD关系。从药效学角度进行药物分析 (有效性和毒性)在猕猴(项目2)和人类(项目3)中的研究，并开发探索性 描述药物暴露-反应关系的药代动力学-药效学(PK-PD)模型 对于每个候选杀菌剂(UC781和替诺福韦)和制剂。

The overarching purpose of this Center Grant, "Alternative Formulations of Tenofovir and UC781" is to develop and compare the performance of two contrasting vaginal microbicide formulation approaches, a gel and a film, as carriers for an antiretroviral drug combination, UC781 and tenofovir (TFV). This project, Project 4, quantitatively explores the PK domain in exploratory clinical studies by way of direct and non-invasive sampling of 6 different compartments within the body - fluid and CD4+ cells components both within the cervicovaginal lumen, cervicovaginal tissues, and blood. The spatlotemporal drug concentration data gathered will be evaluated in light of pharmacodynamic (PD) data, both efficacy and toxicity, from this and other Projects within the Center Grant. Armed with this PK-PD data investigators can reach informed decisions about (1) continued development of these two combination products, (2) potential modifications of the eventual product candidates tested, and (3) rational study design as the candidates enter formal clinical testing. To achieve these objective, we have the following 4 specific aims: Aim 1. Develop and validate assays for UC781, improve tenofovir intracellular assay sensitivity in clinical samples, and verify compatibility of radiolabels with film formulations (Supports Aim 3 & 4 clinical studies) Aim 2. Determine the feasibility of using quantitative changes in cervicovaginal permeability to small molecules and HIV-size particles as a measure of candidate microbicide toxicity: an open label, exploratory clinical study comparing nonoxynol-9 gel to universal placebo. (Needed for support of Specific Aim 3). Aim 3. Compare the spatlotemporal distribution (cervicovaginal and systemic) of candidate film and gel formulations of UC781 (Aim 3-1) and TFV (Aim 3-2): an exploratory clinical study. Aim 4. Exploratory Human and Macaque PK-PD relationships. Perform drug assays from pharmacodynamic (efficacy and toxicity) studies in macaques (Project 2) and humans (Project 3) and develop exploratory pharmacokinetic-pharmacodynamic (PK-PD) models to describe the drug exposure-response relationships for each candidate microbicide (UC781 and tenofovir) and formulation.