Optimizing Combination Therapy to Accelerate Clinical Cure of Tuberculosis

优化联合治疗加速结核病临床治愈

• 批准号: 9750603
• 负责人: George Louis Drusano
• 金额: $ 271.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750603
• 关键词: Acids; Adherence; Animals; Automobile Driving; Bacillus anthracis; Biological Assay; Chemotherapy-Oncologic Procedure; Clinical; Combined Modality Therapy; Complex; Confidence Intervals; Data; Development; Disease; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug Modelings; Endpoint Determination; Evaluation; Fiber; Future; Glean; Goals; Growth; Human; Immunologics; In Vitro; Infection; Link; Macaca; Mathematics; Metabolic; Methods; Microbiology; Modeling; Monte Carlo Method; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; New Agents; Organism; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Positron-Emission Tomography; Predictive Value; Program Research Project Grants; Public Health; Publications; Regimen; Resistance; Rifampin; Schedule; Streptomycin; System; Testing; Therapeutic; Time; Tuberculosis; Validation; Voice; Weight; Work; base; cell killing; chemotherapy; data modeling; design; experimental study; extensive drug resistance; flexibility; high dimensionality; improved; insight; man; mathematical analysis; mathematical model; mortality; mouse model; nonhuman primate; pathogen; patient population; prevent; professor; programs; public health relevance; resistance mechanism; resistant strain; response; screening; simulation; symposium; synergism; therapy duration; tuberculosis drugs; tuberculosis treatment

 DESCRIPTION (provided by applicant): Infection with Mycobacterium tuberculosis (MTB) is a massive worldwide problem. The advent of Multiply Drug- Resistant and eXtensively Drug-Resistant strains (MDR and XDR MTB) has exacerbated the problem and has resulted in increased mortality and substantial morbidity. Other than bedaquiline, which was approved several years ago but with a black box warning, the last "new" MTB agent was rifampin. However, lately a number of new agents, some with unique mechanisms of action have entered the developmental pipeline. This will ultimately help with the therapy of MDR/XDR MTB. A large part of the difficulty in treating MTB is the duration of therapy. Fully susceptible strains requir 6 months of therapy while MDR/XDR strains require 18-24 months of therapy or longer. Such long therapeutic durations exacerbate problems with adherence, which is a major driver of resistance. Further, particularly with MDR/XDR MTB, therapy has many second line agents which are more toxic than first line drugs. It would pay massive public health dividends to be able to shorten therapy. While we have new agents entering the therapeutic armamentarium, little thought has been given to how to use them to improve cell kill, suppress resistance and, hence, have the possibility of shortening therapy. It is the overall goal of this Program to identify optimal regimens that fulfill the requirements of shortening therapy: most rapid cell kill, resistance suppression and activity against different metabolic states in which MTB exists (log-phase growth, acid-phase growth and Non-Replicative Persistent Phenotype-phase). There are three Projects and three Cores. The Projects involve evaluating combinations of MTB drugs in the Hollow Fiber Infection Model (HFIM), in murine models of infection and in the Cynomolgus macaque Non- Human Primate model (NHP). The Cores are the Administrative Core, Drug Assay Core and Mathematical Modeling Core. All Projects and Cores will interact and cross support. The HFIM has the flexibility to study all the metabolic states and to do so with human, murine and NHP drug profiles. A publication from our lab noted that animal drug profiles alter the activity of drugs on the pathogens being modeled. There has been speculation regarding the utility of animal system for reliability to design human trials. We will use the HFIM to generate data on combination therapy kill rates and resistance suppression in each metabolic state, using human and animal profiles. The mathematical modeling will allow direct identification of the impact of the different profiles on endpoints. These HFIM estimates can then be compared to the modeled data in the animal systems. Driving effect parameters with different profiles will allow further insight into what information can be reliably extracted to allow the best bridging to human infection. Sequencing of regimens, with the follow-on regimen being targeted at the organism states remaining after the first regimen and with resistance mechanisms of the two regimens being independent may be the best way to shorten therapy. This can be a general paradigm for future combination regimen development.

 描述（由申请人提供）：结核分枝杆菌（MTB）感染是一个严重的世界性问题。多重耐药和广泛耐药菌株（MDR 和 XDR MTB）的出现加剧了这一问题，并导致死亡率和发病率增加。除了几年前获得批准但带有黑框警告的贝达喹啉外，最后一种“新”MTB 药物是利福平。然而，最近一些具有独特作用机制的新药物已进入开发渠道。这最终将有助于 MDR/XDR MTB 的治疗。治疗 MTB 的很大一部分困难在于治疗的持续时间。完全敏感菌株需要 6 个月的治疗，而 MDR/XDR 菌株需要 18-24 个月或更长时间的治疗。如此长的治疗持续时间加剧了依从性问题，这是耐药性的主要驱动因素。此外，特别是对于 MDR/XDR MTB，治疗有许多比一线药物毒性更大的二线药物。能够缩短治疗时间将带来巨大的公共卫生红利。 虽然我们有新的药物进入治疗设备，但很少有人考虑如何使用它们来改善细胞杀伤、抑制耐药性，从而缩短治疗时间。该计划的总体目标是确定满足缩短治疗要求的最佳方案：最快速的细胞杀伤、耐药性抑制和针对 MTB 存在的不同代谢状态（对数期生长、酸期生长和非复制持续表型期）的活性。 有三个项目和三个核心。该项目涉及在中空纤维感染模型（HFIM）、小鼠感染模型和食蟹猴非人类灵长类动物模型（NHP）中评估 MTB 药物的组合。核心是管理核心、药物分析核心和数学建模核心。所有项目和核心都将交互和交叉支持。 HFIM 可以灵活地研究所有代谢状态，并可利用人类、小鼠和 NHP 药物谱进行研究。我们实验室的一份出版物指出，动物药物概况会改变药物对建模病原体的活性。人们对动物系统在设计人体试验中的可靠性的效用进行了猜测。我们将利用人类和动物概况，使用 HFIM 生成有关每种代谢状态下联合治疗杀灭率和耐药性抑制的数据。数学模型将允许直接识别不同配置文件对端点的影响。然后可以将这些 HFIM 估计值与动物系统中的建模数据进行比较。具有不同配置文件的驱动效果参数将允许进一​​步深入了解可以可靠提取哪些信息，以实现最佳桥接 人类感染。 方案的排序，即后续方案针对第一个方案后剩余的有机体状态，并且两个方案的耐药机制是独立的，可能是缩短治疗时间的最佳方法。这可以成为未来联合治疗方案开发的通用范例。