Clinical optimization of a tenofovir enema and adherence tracking

作为杀菌剂的直肠灌肠(DREAM)计划的开发满足了开发的迫切需要 一种高效、安全和可接受的杀微生物剂灌肠剂，承诺更多的依从性 行为透明的预防直肠艾滋病毒感染的替代方案。该计划的总体目标是 目的：研制一种单剂直肠灌肠，以提供替诺福韦(TFV)前药，能够提供一周的 保护。这一策略建立在以TFV为基础的暴露前预防措施已被证实的高水平有效性的基础上 (PREP)在粘附者中，并直接针对PrEP方案的最大弱点-预防性失败 由于依从性差。鉴于直肠冲洗的常见做法是在接受肛门之前先进行灌肠 性行为，我们选择了一种剂量策略，与其他口服药物相比，这种药物只需要很少或根本不需要改变行为 和主题方法。与口服和口服相比，局部给药还显著减少全身暴露 可注射的方法。我们建议加强药代动力学以提高TFV的生物利用度和 提供持续的释放。三种组织和细胞摄取远高于TFV本身的TFV前药-TFV 富马酸二异丙酯、TFV富马酸丙酮胺(TAF，以前的GS7340)和CMX157-已被选中 为了学习。与梦想计划中的其他3个项目和3个核心相结合，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剂量和灌肠强度的组合最能达到我们的结肠组织 目标药物浓度。 目的2：比较TFV灌肠给药前后的剂量，推荐给药时机及精液对患者的影响。 组织药物浓度。 目的3：评价生物标记物在灌肠剂量和性行为中的应用，以提供客观证据。 遵守规定的剂量。 目的4：提供临床标本(血浆、外周血单核细胞、结肠组织/细胞、直肠液)支持方法 项目2、项目3和核心C中的开发和分析验证。

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.