SMART: A Breath-based Adherence Technology to Monitor HIV Microbicide Gel Use

描述(由申请人提供)：在HIV暴露前预防(PrEP)试验中，口服和杀微生物剂依从性不佳排除了对药物疗效的准确估计。遵守程度的衡量是一项尚未满足的重大挑战。已经测试了杀微生物剂试验中遵守情况的其他客观衡量标准，但没有一项衡量该产品的实际使用情况。我们建议通过利用已经开发的口服剂量技术，为研究杀菌剂给药的研究人员迅速开发一种替代的、基于呼吸的依从性监测工具。Xhale开发了一种基于呼吸的技术，称为SMART(R)(自我监测和报告治疗)依从性系统，使用FDA批准的GRAS调味剂作为依从性使能标记(AEM)，实时监测个体受试者、剂量和口服药物依从性。AEM(如2-丁醇)在不改变其制造工艺或生物利用度的情况下，可轻松安全地并入药品中，在胃和小肠中迅速吸收，并代谢成挥发性代谢物(如2-丁酮)，并在呼气中迅速出现。当受试者通过直接向SMART(R)设备(微型气相色谱仪，MGC)“吹气”来提供呼气样本时，就会拍摄一张面部照片。MGC对这种代谢物(S)的测量明确地证明了特定个人服用口服药物的情况。详细的试验数据存储在MGC设备的本地，并使用无线或蜂窝路由器技术实时传输到中央数据库进行分析。后者是一个基于互联网的数据库，供全球任何地方有互联网连接的授权个人审查。SMART(R)是便携的，设计为可由受试者自行管理。虽然SMART(R)最初是为口服药物设计的，但它可以很容易地适应杀菌剂的文件放置。使用替诺福韦(TFV)凝胶作为模型代理，这笔赠款的目的是构建一种针对杀微生物剂应用进行优化的SMART(R)系统：目标1.在男性(直肠途径)和女性(直肠和阴道途径)中采用交叉设计，确定用于杀微生物剂的最佳AEM(类型和剂量)。(时间：0-12个月)目标2.制定策略(即多管注射器喷涂器)，将最佳的AEM有效地整合到直肠和阴道TFV凝胶的放置中，不需要改变其制造工艺，并保持良好的呼吸标志物的浓度-时间分布。(时间：12-24个月)目标3.优化SMART(R)设备，用于杀微生物剂应用(时间：0-24个月)使用SMART(R)测量杀菌剂依从性，将通过提供实时可操作的依从性数据，对PrEP试验进行最佳分析。通过提供监测杀菌剂依从性的“黄金标准”工具，SMART(R)不仅可以提供卓越的试验数据集，还可以用来识别与依从性差相关的行为，并实施缓解这些行为的策略。1

DESCRIPTION (provided by applicant): In HIV pre-exposure prophylaxis (PrEP) trials sub-optimal oral and microbicide adherence has precluded accurate estimation of drug efficacy. Measurement of adherence is a major, unmet challenge. Other objective measures of adherence in microbicide trials have been tested, but none measure the actual use of the product. We propose to rapidly develop an alternative, breath-based, adherence monitoring tool for investigators studying microbicide administration by leveraging technology already developed for oral dosing. Xhale has developed a breath-based technology, termed the SMART(R) (Self Monitoring and Reporting Therapeutics) Adherence System, to monitor individual subject, dose-by-dose, oral medication adherence in real-time using FDA-approved GRAS flavorants as the adherence enabling marker (AEM). The AEM (e.g., 2- butanol), which is easily and safely incorporated into drug product without altering its manufacturing processes or bioavailability, is rapidly absorbed in the stomach and small intestine, and metabolized to a volatile metabolite (e.g., 2-butanone) that quickly appears in breath. As the subject provides a breath sample by "blowing" directly into the SMART(R) device (miniature gas chromatograph, mGC), a facial picture is taken. Measurement of this metabolite(s) by the mGC unambiguously documents ingestion of oral drugs by a specific individual. Detailed trial data is stored locally i the mGC device and transmitted real-time using wireless or cellular router technology to a central data repository for analysis. The latter is an internet-based database for review by authorized individuals anywhere on the globe with an internet connection. SMART(R) is portable and designed to be self-administered by subjects. Although originally designed for oral drugs, SMART(R) can be easily adapted to document placement of microbicides. Using tenofovir (TFV) gel as a model agent, the aims of this grant are to construct a SMART(R) system optimized for microbicide applications: Aim 1. Using a crossover design in men (rectal route) and women (rectal and vaginal routes), identify an optimal AEM (type and dose) for microbicide applications. (Time: 0-12 months) Aim 2. Develop strategies (i.e., multiple-barrel syringe applicators) to effectively incorporate the optimal AEM into the placement of rectal and vaginal TFV gels that requires no change in their manufacturing processes, and preserves a favorable concentration-time profile of the breath marker. (Time: 12-24 months) Aim 3. Optimize the SMART(R) device for microbicide applications. (Time: 0-24 months) Measurement of microbicide adherence using SMART(R) would allow optimal analysis of PrEP trials by providing real-time actionable adherence data. By providing a "gold standard" tool to monitor microbicide adherence, SMART(R) could not only provide a superior trial dataset, but could also be used to identify behaviors associated with poor adherence and enable strategies to mitigate them. 1