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.

该中心拨款“替诺福韦和 UC781 的替代制剂”的总体目的是 开发并比较两种对比阴道杀微生物剂配方方法的性能，即凝胶 和薄膜，作为抗逆转录病毒药物组合 UC781 和替诺福韦 (TFV) 的载体。这个项目，项目 4、通过直接、非侵入性的方式定量探索探索性临床研究中的PK域 对体内 6 个不同的隔室进行采样 - 液体和 CD4+ 细胞成分均在体内 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，包括功效和毒性。 中心拨款内的其他项目。有了这个 PK-PD 数据，调查人员就可以了解情况 关于 (1) 继续开发这两种组合产品，(2) 的潜在修改的决定 最终的候选产品进行测试，以及（3）候选产品进入正式临床时合理的研究设计 测试。为了实现这些目标，我们有以下 4 个具体目标： 目标 1. 开发并验证 UC781 的检测方法，提高临床中替诺福韦细胞内检测的灵敏度 样品，并验证放射性标记与薄膜配方的兼容性（支持 Aim 3 和 4 临床研究） 目标 2. 确定利用子宫颈阴道通透性的定量变化来调节小范围的可行性 分子和 HIV 大小的颗粒作为候选杀菌剂毒性的衡量标准：开放标签，探索性 比较 nonoxynol-9 凝胶与通用安慰剂的临床研究。 （需要支持具体目标 3）。 目标 3. 比较候选胶片和凝胶的时空分布（宫颈阴道和全身） UC781（目标 3-1）和 TFV（目标 3-2）的制剂：一项探索性临床研究。 目标 4. 探索人类和猕猴 PK-PD 关系。从药效学角度进行药物分析 在猕猴（项目 2）和人类（项目 3）中进行（功效和毒性）研究并开发探索性方法 描述药物暴露-反应关系的药代动力学-药效（PK-PD）模型 每种候选杀菌剂（UC781 和替诺福韦）和配方。