Exploratory Pharmcokinetics of UC781 & Tenofovir Vaginal Microbicide Gel V Film

UC781 的探索性药代动力学

• 批准号: 8660270
• 负责人: Craig Walter Hendrix
• 金额: $ 37.48万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660270
• 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; cervicovaginal; comparative; drug distribution; falls; improved; microbicide; nonhuman primate; open label; pharmacodynamic model; radiotracer; rectal; research clinical testing; response; small molecule; spatiotemporal; success; vaginal microbicide

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.

该中心赠款的首要目的是“替诺福韦和UC 781的替代制剂”， 开发和比较两种对比的阴道杀微生物剂制剂方法的性能， 和薄膜作为抗逆转录病毒药物组合UC 781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通过直接和非侵入性的方式定量探索PK域 对体液内的6个不同隔室进行采样-体液和CD 4+细胞成分， 宫颈阴道腔、宫颈阴道组织和血液。药时数据 将根据药效学（PD）数据（疗效和毒性）对收集的数据进行评价， 中心内的其他项目。有了这些PK-PD数据，研究者可以了解 关于（1）这两种组合产品的持续开发，（2） 最终的候选产品测试，和（3）合理的研究设计，作为候选人进入正式的临床 试验.为了实现这些目标，我们有以下四个具体目标： 目标1.开发并验证UC 781的检测方法，提高替诺福韦细胞内检测的临床灵敏度 样品，并验证放射性标记与薄膜制剂的相容性（支持Aim 3和4临床研究） 目标二。确定使用宫颈阴道通透性定量变化的可行性 分子和HIV大小的颗粒作为候选杀微生物剂毒性的量度：一项开放标签、探索性 壬苯醇醚-9凝胶与通用安慰剂的比较临床研究。（支持具体目标3）。 目标3.比较候选薄膜和凝胶的颞叶分布（宫颈阴道和全身） UC 781（目标3-1）和TFV（目标3-2）制剂：一项探索性临床研究。 目标4。探索性人类和猕猴PK-PD关系。根据药效学进行药物测定 在猕猴（项目2）和人类（项目3）中进行（疗效和毒性）研究，并开发探索性 药代动力学-药效学（PK-PD）模型，用于描述药物的安全性-反应关系 每种候选杀微生物剂（UC 781和替诺福韦）和制剂。