Clinical optimization of a tenofovir enema and adherence tracking

替诺福韦灌肠和依从性跟踪的临床优化

• 批准号: 8768695
• 负责人: Craig Walter Hendrix
• 金额: $ 102.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768695
• 关键词: Address; Adherence; Anal Sex; Anatomy; Anus; Autologous; Behavioral; Bilirubin; Biological; Biological Assay; Biological Availability; Biological Markers; CD4 Positive T Lymphocytes; Cells; Clinic; Clinical; Clinical Research; Colon; Computers; Critical Pathways; Crossover Design; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug Targeting; Drug or chemical Tissue Distribution; Electronics; Event; Failure; Fumarates; Future; Gel; Goals; HIV; HIV Infections; High Risk Woman; Hour; Injectable; Liquid substance; Macaca; Methods; Metric; Monitor; Oral; Outcome; Outpatients; Participant; Patients; Performance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Physiological; Plasma; Prevention; Prodrugs; Prophylactic treatment; Protocols documentation; Records; Recruitment Activity; Regimen; Relative (related person); Research; Sampling; Seminal fluid; Sensitivity and Specificity; Series; Sex Behavior; Signal Transduction; Silicones; Simulate; Skin; System; Tenofovir; Tenofovir disoproxil fumarate; Testing; Time; Tissue Model; Tissues; Toxic effect; Vaginal Douching; Validation; Work; assay development; base; design; enema administration; healthy volunteer; men; method development; microbicide; phase 1 study; pre-clinical; programs; prophylactic; rectal; sex; uptake

The Development of a Rectal Enema As Microbicide (DREAM) Program addresses the critical need to develop a highly effective, safe, and acceptable microbicide enema with the promise of greater adherence as a more behaviorally-transparent alternative for the prevention of rectal HIV infection. The overall goal of the program is to develop a single dose rectal enema to deliver a tenofovir (TFV) prodrug capable of providing one week of protection. This strategy builds upon proven high levels of efficacy of TFV-based pre-exposure prophylaxis (PrEP) in adherent persons and directly targets the greatest weakness of PrEP regimens - prophylactic failure due to poor adherence. Given the common practice of rectal douching with an enema prior to receptive anal sex, we have selected a dosing strategy which requires little or no behavioral change compared to other oral and topical approaches. Topical delivery also significantly reduces systemic exposure compared to oral and injectable approaches. We propose pharmacokinetic enhancements to increase TFV bioavailability and provide sustained release. Three TFV prodrugs with far greater tissue and cellular uptake than TFV itself - TFV disoproxil fumarate, TFV alafenamide fumarate (TAF, formerly GS7340), and CMX157 - have been selected for study. Integrated with 3 other projects and 3 cores in the DREAM Program, Project 1 involves a series of clinical studies to achieve the following specific aims: Aim 1: Determine the combination of TFV dose and enema tonicity best able to achieve our colon tissue target drug concentrations. Aim 2: Compare TFV enema dosing before and after to recommend dose timing and the impact of semen on tissue drug concentrations. Aim 3: Evaluate the use of biomarkers for both enema dosing and sexual activity to provide objective evidence of adherence to protocol prescribed dosing. Aim 4: Provide clinical samples (plasma, PBMC, colon tissue/cells, rectal fluid) to support method development and assay validation in Project 2, Project 3, and Core C.

直肠灌肠作为菌心（DREAM）计划的开发解决了发展的关键需求 高效，安全且可接受的杀菌剂灌肠，并承诺更大的依从性 行为透明的替代方案，可预防直肠HIV感染。该计划的总体目标是 开发单剂直肠灌肠以提供替诺福韦（TFV）前药，能够提供一周的时间 保护。该策略建立在可证明的基于TFV的预防前预防的高效力的基础上 （PREP）在依从者中，直接针对预防治疗方案的最大弱点 - 预防性衰竭 由于依从性不佳。鉴于在接受肛门之前用灌肠直肠冲洗的常见做法 性别，我们选择了一种给药策略，与其他口头相比，几乎不需要行为的变化 和局部方法。与口头相比，局部交付还大大降低了全身性暴露 注射方法。我们提出了药代动力学增强功能，以提高TFV生物利用度和 提供持续的释放。三个TFV前药具有比TFV本身更大的组织和细胞摄取的前药-TFV 已经选择了毒氧化毒素，TFV Alafenamide Fumarate（TAF，以前为GS7340）和CMX157- 进行研究。项目1与其他3个项目和3个核心集成在一起，涉及一系列 临床研究以实现以下特定目的： AIM 1：确定TFV剂量和灌肠滋补的结合，最能实现我们的结肠组织 目标药物浓度。 AIM 2：比较TFV灌肠前后的剂量，以推荐剂量时序以及精液对 组织药物浓度。 目标3：评估生物标志物作为灌肠剂量和性活动的使用以提供客观证据 遵守规定剂量的协议。 AIM 4：提供临床样品（血浆，PBMC，结肠组织/细胞，直肠液）以支持方法 项目2，项目3和CoreC的开发和测定验证。