Integrative Pharmacology Approach to Understand Mechanisms of TB Drug Resistance

了解结核病耐药机制的综合药理学方法

• 批准号: 8709773
• 负责人: Kelly E. Dooley
• 金额: $ 65.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709773
• 关键词: Accounting; Adherence; Animal Model; Antitubercular Agents; Biological Models; C3HeB/FeJ Mouse; Clinic; Clinical; Clinical Microbiology; Clinical Trials; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Complex; Data; Development; Disease; Dose; Drug Combinations; Drug Exposure; Drug Resistant Tuberculosis; Drug resistance; Drug usage; Emergency Situation; Ethambutol; Family; Fiber; Frequencies; Future; Gene Mutation; Genes; Human; Human Pathology; Immune; Immunity; Immunocompetent; Immunodeficient Mouse; In Vitro; Inbred BALB C Mice; Injectable; Intervention; Lesion; Lung; Measurement; Modeling; Moxifloxacin; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; Necrosis; New Agents; Nitroimidazoles; Nude Mice; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase II/III Trial; Plasma; Population; Pre-Clinical Model; Prevention; Pulmonary Tuberculosis; Pyrazinamide; Pyrazinamide resistance; Regimen; Resistance; Rifampin; Risk; Route; Schedule; Site; Sputum; System; Testing; Time; Tissues; Treatment Protocols; Tuberculosis; Update; base; data modeling; drug development; drug distribution; global health; inhibitor/antagonist; innovation; isoniazid; killings; mathematical model; mortality; mouse model; multi-scale modeling; mutant; novel; pathogen; pre-clinical; predictive modeling; prevent; public health relevance; research study; success; tool; treatment trial; tuberculosis drugs; tuberculosis treatment

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.

描述（应用程序提供）：多药（MDR-）结核病有可能破坏治疗这种病态疾病的进展。当前的治疗方案是有毒的，需要进行20个月的治疗，仅治愈约50％的患者。 50年来，有7种不同类别的新药是结核病的临床开发，可能提供了包含2个或更多新型类别的转型新方案。实际上，ATP合酶抑制剂Bedaquiline最近被批准用于治疗MDR-TB，并且在II/III期试验中，正在接受MDR-TB和两个硝基咪唑衍生物（即PA-824和Delamanid）。尽管确保对组合疗法的依从性仍然是预防抗性的重要方面，但新兴的证据表明，防止MDR-TB和/或保护新药物免受紧急阻力的最佳策略应包括优化的药物给药，剂量调度和方案组成。然而，当前的药物开发工作在很大程度上忽略了疗法的“耐用性”，即疗法对抗药性出现的鲁棒性。我们提出了一个新型的翻译平台，用于使用多尺度建模或综合药理学方法评估和优化结核病方案的耐用性，该方法考虑了决定耐药性出现的宿主，病原体和药物相关因素的相互作用。结合体外组合时间杀伤性研究，在3个鼠模型（常规BALB/c小鼠，免疫缺陷裸体小鼠中，与C3H3B/Mycobacter inters intersy的新型Cavitary TB）中，在体外药效系统（中空纤维模型）（中空纤维模型）和多饮用方法中进行了实验，并在多种洞穴模型中进行了多次治疗试验。基于PA-824，Moxifloxacin和吡嗪酰胺（Bedaquiline）的组合，在当前一线方案和新型方案的背景下出现了抗性。我们将（1）开发一个模型框架，用于确定在结合化疗期间使用体外时间杀伤性研究，一种体外药物学系统以及Balb/c小鼠（2）探索宿主选择的宿主选择者（2），使用小鼠的宿主选择（2），使用小鼠（2），使用小鼠模型（2）探索了骑士的模型TILMARY T）（（2）免疫状态），通过测量受感染组织中结核病药物的组织浓度，以评估效应部位的药物浓度； （3）评估干预措施，以降低使用体外和小鼠实验的抗抗病治疗方案的抗药性风险。综合建模方法将用于合成和解释我们实验中出现的多尺度数据（宿主，病原体，药物）。结果将用于告知药物干预措施，以降低MDR-TB的风险和对珍贵的新抗TB药物的抵抗。将努力使用来自新型结核病治疗方案的临床试验中的数据来验证模型。我们开发的集成药理学平台将是一种新颖的工具，可以通过新兴信息进行更新，并用于系统地评估未来结核病方案的耐用性。