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: 9529494
• 负责人: George Louis Drusano
• 金额: $ 233.3万
• 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/9529494
• 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（由适用提供）：结核分枝杆菌（MTB）感染是全球范围内的一个巨大问题。抗药性和广泛抗药性菌株的冒险（MDR和XDR MTB）加剧了该问题，并导致死亡率和大量发病率增加。除了几年前获得批准的Bedaquiline，但带有黑匣子警告，最后一个“新” MTB特工是Rifampin。但是，最近一些新代理人，有些具有独特作用机制的机理已进入了发展管道。这最终将有助于MDR/XDR MTB的治疗。治疗MTB的很大一部分是治疗的持续时间。完全易感性菌株需要6个月的治疗，而MDR/XDR菌株需要18-24个月的治疗或更长的时间。如此长的治疗持续时间加剧了依从性的问题，它将为能够缩短疗法带来巨大的公共卫生股息。此外，尤其是在MDR/XDR MTB的情况下，治疗具有许多二线药物，它们比一线药物更具毒性。 虽然我们有新的代理商进入治疗性武术，但几乎没有想到如何使用它们来改善细胞杀伤，抑制耐药性，因此具有缩短治疗的可能性。该计划的总体目标是确定满足缩短疗法要求的最佳方案：对MTB存在的不同代谢状态的最快细胞杀死，耐药性抑制和活性（对数相位生长，酸性期生长，非复制性持久性表型）。 有三个项目和三个核心。这些项目涉及在空心纤维感染模型（HFIM），感染的鼠模型和Cynomolgus猕猴非人类灵长类动物模型（NHP）中评估MTB药物的组合。核心是行政核心，药物测定核心和数学建模核心。所有项目和核心都将互动和交叉支持。 HFIM具有研究所有代谢状态的灵活性，并使用人，鼠和NHP药物谱进行。我们实验室的出版物指出，动物药物谱改变了药物对正在建模的病原体的活性。关于动物系统对设计人体试验的可靠性的效用，人们一直存在猜测。我们将使用HFIM使用人和动物谱来生成有关每个代谢状态中组合疗法杀伤率和抗药性抑制的数据。数学建模将允许直接识别不同轮廓对端点的影响。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驾驶效应参数将可以进一步深入了解哪些信息可以可靠地提取，以使最佳的桥梁到达最佳的桥梁 人类感染。 疗法的测序是，后续方案是针对第一个方案后仍保留的生物体，并且具有独立的两个方案的耐药机制可能是缩短治疗的最佳方法。这可能是未来组合方案开发的一般范式。