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.

直肠灌肠作为杀微生物剂（梦想）计划的发展解决了发展的迫切需要， 一种高效，安全，可接受的杀微生物剂灌肠剂，作为一种 行为透明的替代品，用于预防直肠艾滋病毒感染。该计划的总体目标是 开发单剂量直肠灌肠剂以递送能够提供一周的替诺福韦（TFV）前药， 保护该策略建立在已证实的基于TFV的暴露前预防的高水平疗效基础上 （PrEP）在坚持的人，并直接针对PrEP方案的最大弱点-预防性失败 由于粘附性差。考虑到在接受肛门前用灌肠剂进行直肠冲洗的常见做法， 性别，我们选择了一种给药策略，与其他口服给药策略相比， 和专题方法。与口服给药相比，局部给药还显著降低了全身暴露， 注射方法。我们提出了药代动力学增强，以增加TFV的生物利用度， 提供持续释放。三种TFV前药的组织和细胞摄取远大于TFV本身-TFV 已选择富马酸二异山梨酯、TFV富马酸艾拉酚胺（TAF，以前称为GS 7340）和CMX 157- 为了学习结合其他3个项目和梦想计划的3个核心，项目1涉及一系列 临床研究，以实现以下具体目标： 目的1：确定TFV剂量和灌肠张力的组合，最好能够达到我们的结肠组织 目标药物浓度。 目的2：比较TFV灌肠剂给药前后，以推荐给药时机和精液对 组织药物浓度。 目的3：评价生物标志物在灌肠剂量和性活动中的使用，以提供客观证据 遵守方案规定的剂量。 目的4：提供临床样本（血浆、PBMC、结肠组织/细胞、直肠液）以支持方法 项目2、项目3和核心C中的开发和试验验证。