Integrative Pharmacology Approach to Understand Mechanisms of TB Drug Resistance

描述(申请人提供)：多药耐药(MDR-)结核病可能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个月的服药时间，只有大约50%的患者被治愈。50年来，来自4个不同类别的7种新药正在进行结核病临床开发，这是50年来的第一次，并可能提供包含2个或更多新类别的变革性新疗法。事实上，三磷酸腺苷合成酶抑制剂贝达奎林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)正处于II/III期试验。虽然确保坚持联合治疗仍然是耐药预防的一个重要方面，但新出现的证据表明，预防耐多药结核病和/或防止新药物出现耐药的最佳策略应该包括优化药物剂量、剂量安排和方案组成。然而，目前的药物开发努力在很大程度上忽视了方案的“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，用于使用多尺度建模或综合药理学方法来评估和优化结核病方案的持久性，该方法考虑了宿主、病原体和药物相关因素的相互作用，这些因素决定了耐药的出现。使用体外联合时间杀灭研究、体外药效系统实验(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小鼠新型空洞型结核病模型)和多种结核分枝杆菌(MTB)菌株的多药治疗试验相结合的方法，确定在当前一线方案和基于PA-824、莫西沙星和吡嗪酰胺(贝达奎林)组合的新型方案的背景下，耐药性出现的决定因素。我们将(1)利用体外时间-杀伤研究、体外药效学系统和BALB/c小鼠建立用于确定联合化疗中异烟肼和利福平耐药的药理学和细菌学决定因素的模型框架；(2)利用空洞型肺结核病(病理影响)和裸鼠(免疫状态的影响)小鼠模型，通过测量结核药物在感染组织中的组织浓度来评估作用部位的药物浓度，以探索与宿主相关的耐药决定因素；以及(3)使用体外实验和小鼠实验评估干预措施，以减少对包括PA-824和贝达奎兰在内的新治疗方案出现耐药性的风险。将使用一种综合建模方法来合成和解释从我们的实验中出现的多尺度数据(宿主、病原体、药物)。结果将被用于提供药物干预措施，以降低耐多药结核病的风险和对宝贵的抗结核新药的耐药性。将努力利用正在进行的一项新结核病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个新的工具，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.