Integrative Pharmacology Approach to Understand Mechanisms of TB Drug Resistance

描述（由申请人提供）：耐多药（MDR-）结核病威胁着破坏在治疗这种病态疾病方面取得的进展。目前的治疗方案是有毒的，需要20个月的管理和治愈只有约50%的患者。50年来，来自4个不同类别的7种新药首次进入结核病临床开发阶段，并可能提供包含2种或更多新类别的转型新方案。事实上，ATP合成酶抑制剂贝达喹啉最近被批准用于治疗MDR-TB和两种硝基咪唑衍生物（即，PA-824和delamanid）处于II/III期试验中。尽管确保坚持联合治疗仍然是耐药性预防的一个重要方面，但新出现的证据表明，预防耐多药结核和/或保护新药不出现耐药性的最佳策略应包括优化药物剂量、剂量安排和方案组成。然而，目前的药物开发工作在很大程度上忽视了方案的“持久性”，即方案对耐药性出现的稳健性。我们提出了一种新的翻译平台，用于评估和优化结核病治疗方案的持久性，使用多尺度建模或综合药理学方法，该方法考虑到宿主，病原体和药物相关因素的相互作用，这些因素决定了耐药性的出现。使用体外联合时间-杀灭研究的组合，体外药效学系统的实验（中空纤维模型）和3种鼠模型中的多药治疗试验（常规BALB/c小鼠，免疫缺陷裸鼠，和C3 H3 B/FeJ小鼠中的新型空腔TB模型），使用多种结核分枝杆菌（MTB）菌株，以确定在当前第一阶段背景下出现耐药的决定因素。线方案和基于PA-824、氟沙星和吡嗪酰胺（β贝达喹啉）组合的新方案。我们将（1）使用体外时间-杀灭研究、体外药效学系统和BALB/c小鼠，开发一个模型框架，用于确定联合化疗期间选择对异烟肼和利福平耐药的药理学和细菌学决定因素，（2）利用空洞型肺结核小鼠模型探讨宿主相关的耐药选择决定因素（病理学影响）和裸鼠（免疫状态的影响），测量结核药物在感染组织中的组织浓度，以评估作用部位的药物浓度;和（3）使用体外和小鼠实验评价干预措施，以降低对涉及PA-824和贝达喹啉的新型治疗方案出现耐药性的风险。一个综合的建模方法将被用来合成和解释多尺度数据（主机，病原体，药物），从我们的实验中出现。研究结果将用于指导药物干预，以降低耐多药结核病的风险和对宝贵的新型抗结核药物的耐药性。将努力使用一项正在进行的新型结核病治疗方案临床试验的数据来验证该模型。我们开发的综合药理学平台将是一种新的工具，可以根据新出现的信息进行更新，并用于系统地评估未来TB方案的持久性。

DESCRIPTION (provided by applicant): Multidrug-resistant (MDR-) TB threatens to undermine the progress made in treating this morbid disease. Current treatment regimens are toxic, and require � 20 months of administration and cure only about 50% of patients. For the first time in 50 years, 7 new drugs from 4 different classes are in clinical development for TB and may provide for transformational new regimens containing 2 or more novel classes. Indeed, bedaquiline, an ATP synthase inhibitor, was recently approved to treat MDR-TB and two nitroimidazole derivatives (i.e., PA-824 and delamanid) are in phase II/III trials. Although assuring adherence to combination therapy remains an important aspect of resistance prevention, emerging evidence suggests that optimal strategies for preventing MDR-TB and/or protect new agents against emergence of resistance should include optimized drug dosing, dose scheduling, and regimen composition. Yet current drug development efforts largely ignore the "durability" of regimens, that is, the robustness of regimens to emergence of resistance. We propose a novel translational platform for evaluating and optimizing the durability of TB regimens using a multiscale modeling, or integrative pharmacology, approach that takes into account the interaction of host, pathogen, and drug-related factors which determine the emergence of drug resistance. Using a combination of in vitro combination time-kill studies, experiments in an in vitro pharmacodynamic system (hollow fiber model), and multidrug treatment trials in 3 murine models (conventional BALB/c mice, immunodeficient nude mice, and a novel cavitary TB model in C3H3B/FeJ mice) with multiple Mycobacterium tuberculosis (MTB) strains to define the determinants of resistance emergence in the context of the current 1st-line regimen and novel regimens based on the combination of PA-824, moxifloxacin and pyrazinamide (� bedaquiline). We will (1) develop a model framework for determining the pharmacological and bacteriological determinants of selection of resistance to isoniazid and rifampin during combination chemotherapy using in vitro time-kill studies, an in vitro pharmacodynamic system, and BALB/c mice, (2) explore host-related determinants of resistance selection using a mouse model of cavitary pulmonary TB (effects of pathology) and nude mice (effects of immune status), with measurement of tissue concentrations of TB drugs in infected tissues to assess drug concentrations at the effect site; and (3) evaluate interventions to reduce the risk of emergence of resistance to novel treatment regimens involving PA-824 and bedaquiline using in vitro and mouse experiments. An integrative modeling approach will be used to synthesize and interpret the multiscale data (host, pathogen, drug) that emerge from our experiments. Results will be used to inform pharmacological interventions to reduce the risk of MDR-TB and resistance to precious new anti-TB drugs. An effort will be made to validate the model using data from an ongoing clinical trial of a novel TB regimen. The integrative pharmacology platform we develop will be a novel tool that can be updated with emerging information and used to systematically assess the durability of future TB regimens.