Integrative Pharmacology Approach to Understand Mechanisms of TB Drug Resistance

描述（由申请人提供）：耐多药（MDR-）结核病威胁着在治疗这一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个月的治疗，而且只有大约50%的患者能治愈。50年来第一次，来自4个不同类别的7种结核病新药正在临床开发中，并可能提供包含2个或更多新类别的变革性新方案。事实上，ATP合成酶抑制剂贝达喹啉最近被批准用于治疗耐多药结核病，两种硝基咪唑衍生物（即PA-824和delamanid）正在进行II/III期试验。尽管确保坚持联合治疗仍然是预防耐药性的一个重要方面，但新出现的证据表明，预防耐多药结核病和/或保护新药不产生耐药性的最佳策略应包括优化药物剂量、剂量计划和方案组成。然而，目前的药物开发工作在很大程度上忽略了方案的“持久性”，即方案对出现耐药性的稳健性。我们提出了一个新的翻译平台，利用多尺度建模或综合药理学方法来评估和优化结核病治疗方案的持久性，该方法考虑了宿主、病原体和决定耐药性出现的药物相关因素的相互作用。通过体外联合时间杀伤研究、体外药理学系统实验（中空纤维模型）和3种小鼠模型（常规BALB/c小鼠、免疫缺陷裸鼠和C3H3B/FeJ小鼠新型空洞结核模型）的多药治疗试验，确定当前一线方案和基于PA-824联合的新型方案下耐药产生的决定因素。莫西沙星和吡嗪酰胺（贝达喹啉）。我们将(1)建立一个模型框架，利用体外时间杀伤研究、体外药效学系统和BALB/c小鼠，确定联合化疗期间异烟肼和利福平耐药性选择的药理学和细菌学决定因素；(2)利用空腔性肺结核小鼠模型（病理学影响）和裸鼠（免疫状态影响），探索耐药性选择的宿主相关决定因素。测量感染组织中结核药物的组织浓度，以评估作用部位的药物浓度；(3)通过体外和小鼠实验评估干预措施，以降低对PA-824和贝达喹啉的新治疗方案出现耐药性的风险。综合建模方法将用于综合和解释我们实验中出现的多尺度数据（宿主，病原体，药物）。研究结果将用于为药理学干预提供信息，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。将努力利用正在进行的一种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成为一种新的工具，可以根据新出现的信息进行更新，并用于系统地评估未来结核病治疗方案的持久性。

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.