Novel methods of pharmacologic monitoring for multidrug resistant tuberculosis treatment in the setting of HIV infection

 描述(申请人提供)：耐多药结核病(MDR-TB)是一种新出现的全球公共卫生危机。目前对耐多药结核病的治疗需要至少18个月的二线药物，这些药物具有几十年的潜在毒性和低效，往往以治疗失败或死亡告终。尤其是在艾滋病毒合并感染的情况下，耐多药结核病的治疗因药片负担增加、重叠的药物毒性和高死亡率而变得复杂。大量的财政和科学资源被用于研究耐多药结核病的新药，但由于对每种药物对多药方案的单独贡献、每种药物的暴露-反应关系以及如何最好地识别治疗无效的患者缺乏了解，优化和缩短治疗的努力受到了严重阻碍。此外，鉴于耐多药结核病治疗越来越多地在社区环境中提供，需要更好的工具来评估遵守情况和监测治疗情况，以改善个人结果和减少传播。在临床试验和高危患者(如同时患有耐多药结核病和艾滋病毒的人)中进行常规药理学监测的一个主要障碍是，目前监测药物暴露(即血浆水平)的方法需要静脉采血、冷链，而且通常不够频繁地重复，无法表征随着时间的推移药物暴露的特征。此外，在直接观察到的剂量之后，高剂量后暴露在血浆中不能确认长期坚持。我们提出这项研究的目的是要确定，在耐多药结核病的两个主要临床试验中，对一组二线结核病药物浓度的评估是否将提高我们预测耐多药结核病患者治疗失败、获得性耐药性或死亡的能力，尤其是那些同时感染艾滋病毒的患者。小毛发样本中的药物浓度代表之前1-2个月内的药物暴露，收集是非侵入性的，不需要静脉抽液、无菌设备、生物危害预防措施或冷藏。我们建议将UCSF在开发抗逆转录病毒暴露监测的头发分析方面的专业知识首次扩展到耐多药结核病，将我们的研究嵌入由NIH支持的贝达奎林和delamanid安全性和药代动力学的第二阶段试验中-这是50多年来专门为治疗结核病而创建的第一种新药类别-以及由南非医学研究理事会支持的第三阶段务实随机对照试验，该试验检验了一种新型的6个月、不注射的MDR-TB方案的有效性。头发中的药物浓度将在一个关键的二线结核病药物的多重小组中进行分析，包括贝达奎兰和地拉曼德。通过密集的开发和验证研究，涉及到血浆药代动力学、依从性测量和临床结果的相关性，我们拟议的工作可能对

 DESCRIPTION (provided by applicant): Multidrug resistant tuberculosis (MDR-TB) is an emerging global public health crisis. Current treatment of MDR-TB requires at least 18 months of decades-old, potentially toxic, and poorly efficacious second-line drugs, too often ending in treatment failure or death. Treatment of MDR-TB in the setting of HIV co-infection, in particular, is complicated by increased pill burden, overlapping drug toxicities, and high mortality. Tremendous financial and scientific resources are directed toward investigation of new drugs for MDR-TB, but efforts to optimize and shorten treatment are hindered significantly by a poor understanding of the individual contribution of each drug to a multidrug regimen, the exposure-response relationship for each drug, and how to best identify those patients who are failing to respond to treatment. In addition, given that MDR-TB treatment is increasingly provided in community settings, better tools are needed to assess adherence and monitor therapy in order to improve individual outcomes and reduce transmission. A major barrier to routine pharmacologic monitoring within clinical trials and among high-risk patients (such as persons with concomitant MDR-TB and HIV) is that current methods to monitor medication exposure (i.e., plasma levels) require phlebotomy, a cold chain, and are generally not repeated frequently enough to characterize drug exposure over time. Moreover, high post-dose exposure in plasma after a directly-observed dose cannot confirm long-term adherence. Our goal in proposing this study is to determine whether an assessment of a panel of second-line TB drug concentrations in small hair samples, an easily accessible biomatrix, determined via liquid-chromatography /tandem mass-spectrometry will improve our ability to predict the risk of treatment failure, acquired drug resistance, or death in patients with MDR-TB, with a particular emphasis on those with HIV co-infection, in two major clinical trials of MDR-TB. Drug concentrations in small hair samples represent drug exposure over the preceding 1-2 months, and collection is noninvasive without need for phlebotomy, sterile equipment, biohazard precautions, or cold storage. We propose to extend our expertise at UCSF in developing hair assays for antiretroviral exposure monitoring for the first time to MDR-TB, embedding our studies within an NIH-supported phase II trial of the safety and pharmacokinetics of bedaquiline and delamanid - the first new drug classes created specifically to treat TB in over 50 years - and a South African Medical Research Council-supported phase III pragmatic randomized controlled trial examining the effectiveness of a novel 6-month, injectable-free MDR-TB regimen. Drug concentrations in hair will be analyzed in a multiplex panel of key second-line TB drugs, including bedaquiline and delamanid. Through intensive development and validation studies involving correlation with plasma pharmacokinetics, adherence measures, and clinical outcomes, our proposed work may have far-reaching implications for