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.

本中心资助“替诺福韦和UC781的替代配方”的总体目的是