Exploratory Pharmcokinetics of UC781 & Tenofovir Vaginal Microbicide Gel V Film

UC781 的探索性药代动力学

• 批准号: 7898237
• 负责人: Craig Walter Hendrix
• 金额: $ 33.54万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898237
• 关键词: Anatomic Sites; Anti-Retroviral Agents; Biological; Biological Assay; Biological Markers; Blood; Body Fluids; CD4 Positive T Lymphocytes; Cells; Cellular Structures; Clinical; Clinical Research; Data; Detergents; Development; Diphosphates; Dose; Drug Combinations; Drug Exposure; Drug Formulations; Drug Kinetics; Drug effect disorder; Female; Film; Future; Gel; Genital system; Grant; HIV; HIV Infections; Hour; Human; Image; Indium; Light; Liquid substance; Macaca; Measures; Modification; Mucous Membrane; Nonoxynol 9; Oral; Outcome Study; Particle Size; Pattern; Penetration; Performance; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Predisposition; Preventive; Radiolabeled; Recruitment Activity; Research Design; Research Personnel; Sampling; Schedule; Site; Technetium; Tenofovir; Tenofovir disoproxil fumarate; Testing; Time; Tissue Banking; Tissue Banks; Tissues; Toxic effect; UC 781; Vagina; Validation; Woman; arm; comparative; drug distribution; falls; improved; microbicide; nonhuman primate; open label; pharmacodynamic model; radiotracer; rectal; research clinical testing; response; small molecule; success; vaginal microbicide

The overarching purpose ofthis 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.

此中心赠款的总体目的是“ Tenofovir and UC781的替代表述”是 开发和比较两种对比鲜明的阴道杀微生物配方方法的性能，一种凝胶 膜，作为抗逆转录病毒药物组合的载体，UC781和Tenofovir（TFV）。这个项目，项目 4，通过直接和无创的方式定量探索探索性临床研究中的PK结构域 体内6种不同的隔室的采样 - 流体和CD4+细胞组件都在 宫颈阴道腔，宫颈阴道组织和血液。时空药物浓度数据 收集的将根据药效学（PD）数据（疗效和毒性）进行评估。 中心赠款中的其他项目。由此PK-PD数据调查人员武装起来 关于（1）这两种组合产品的持续开发的决定，（2）潜在的修改 最终测试的产品候选者以及（3）候选人进入正式临床时的合理研究设计 测试。为了实现这些目标，我们有以下4个特定目标： AIM 1。开发和验证UC781的测定，提高替诺福韦的细胞内测定敏感性 样品，并验证放射性标记与膜制剂的兼容性（AIMS AIM 3和4临床研究） AIM 2。确定在宫颈阴道通透性中使用定量变化对小的可行性 分子和艾滋病毒大小的颗粒作为候选菌心毒性的量度：开放标签，探索性 临床研究比较了非氧合-9凝胶与通用安慰剂。 （支持特定目标3）。 AIM 3。比较候选膜和凝胶的时空分布（宫颈阴道和全身性） UC781（AIM 3-1）和TFV（AIM 3-2）的配方：一项探索性临床研究。 目标4。探索性人和猕猴PK-PD关系。从药效学进行药物测定 （功效和毒性）猕猴（项目2）和人类（项目3）的研究并发展探索性 药代动力学 - 药物动力学（PK-PD）模型来描述药物暴露 - 响应关系 对于每种候选菌心（UC781和Tenofovir）和配方。