Combination Therapy Modeling for M tuberculosis Resistance Suppression and Kill

描述（由申请人提供）：结核分枝杆菌（Mtb）感染全球超过20亿人，每年导致140万人死亡。由于药物敏感性Mtb引起的结核病（TB）的标准治疗包括2个月的利福平（RIF）、异烟肼（INH）、吡嗪酰胺（PZA）和乙胺丁醇（EMB），随后是4个月的RIF和INH。在临床TB患者中，Mtb存在3种代谢状态：对数生长期、半休眠酸性期和非复制持续（NRP）状态。NRP Mtb需要长期治疗才能杀死，并导致疾病复发。RIF、INH和EMB杀死对数生长期Mtb，而PZA杀死酸性相Mtb。RIF也杀死NRP Mtb。因此，标准方案中仅一种药物对酸性相和NRP Mtb有活性。多药耐药结核病（MDR-TB）的流行率正在上升，这是由于使用经验性抗生素组合治疗由对先验方案中的一种或多种药物具有耐药性的微生物引起的结核病，即使在直接观察治疗下也会出现药物给药错误，以及患者不遵守长期治疗过程。在将具有新作用机制的新抗生素添加到药物敏感性结核分枝杆菌和耐多药结核分枝杆菌的标准方案中的研究中，动物模型中细菌灭菌的时间和临床试验中痰液转化为阴性的时间缩短了，表明由标准一线和二线结核分枝杆菌药物组成的方案没有优化以杀死结核分枝杆菌。我们的长期目标是开发更好的结核病治疗方案。总体假设是，经过药效学（PD）优化以杀死所有3种代谢状态的Mtb并防止敏感性较低的细菌亚群扩增的TB方案将提供有效的疗程较短的TB方案，从而改善治疗结果并降低耐药性。我们将测试这一假设，并通过完成以下具体目标来制定一个高效的短期方案：具体目标#1。在体外中空纤维感染模型（HIBR）中模拟3种在所有代谢状态下具有活性的新型TB抗生素的临床相关剂量的游离肺PK特征，确定每种药物的P指数、药物暴露和给药间隔，其PD优化了3种代谢状态中每种状态下DS-Mtb的杀灭速度和程度。确定这些单一药物方案是否可以预防耐药性。具体目标#2。当特定目标#1中开发的PD优化方案用作2种和3种药物组合时，比较3种代谢状态下DS-Mtb的杀灭率和程度，以及这些抗生素对易感性较低的Mtb人群的影响。采用创新的数学模型来确定3种药物方案中每种抗生素的给药剂量和频率，预计通过优化每种代谢状态下的Mtb杀灭和预防耐药性，为人类结核病的治疗提供疗程更短、高效的方案。具体目标#3使用阻滞剂，表征PD优化的3种药物方案对耐1种药物组分的菌株在3种代谢状态下杀灭Mtb的速率和程度的有效性。 具体目标#4普罗帕酮验证了创新的PD优化的3种药物方案在肺TB的新型鼠模型中的性能，其中对数期、酸性期和NRP状态的Mtb共存，以及在另一种创新的TB体内模型中使用最先进的给药算法，该算法使动物中产生的PK特征“人源化”。使用新型鼠模型表征该方案杀灭DS-和MDR-TB的相对有效性。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) infects over 2 billion people worldwide and causes 1.4 million deaths annually. The standard treatment for tuberculosis (TB) due to drug-susceptible Mtb consists of 2 months of rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) followed by 4 months of RIF and INH. In patients with clinical TB, Mtb exists in 3 metabolic states: log phase growth, semi-dormant acidic phase, and a non-replicating persister (NRP) state. NRP Mtb requires prolonged therapy to kill and is responsible for disease relapse. RIF, INH and EMB kill log phase growth Mtb, while PZA kills acidic phase Mtb. RIF also kills NRP Mtb. Thus, only one drug in the standard regimen is active against acidic phase and NRP Mtb. The prevalence of multidrug resistant Mtb (MDR-TB) is rising due to the use of empiric antibiotic combinations for TB caused by microbes that are resistant to one or more drugs in the regimen a priori, errors in the administration of the medications even under Direct Observed Therapy, and patient non-compliance with the long treatment course. In studies in which new antibiotics with novel mechanisms of action are added to the standard regimen for drug-susceptible Mtb and MDR-TB the time to bacterial sterilization in animal models and the time for sputum conversion to negative in clinical trials are shortened, showing that regimens consisting of the standard first and second line TB drugs are not optimized to kill Mtb. Our long term objective is to develop improved TB regimens. The overarching hypothesis is that TB regimens that are pharmacodynamically (PD) optimized to kill Mtb in all 3 metabolic states and to prevent amplification of less-susceptible bacterial subpopulations will provide a potent shorter course TB regimen that will improve treatment outcomes and reduce resistance. We will test this hypothesis and develop a highly effective short course regimen by completing the following Specific Aims: Specific Aim #1. Simulating in an in vitro hollow fiber infection model (HFIM) the free pulmonary PK profiles for clinically relevant doses of 3 novel TB antibiotics that have activity in all metabolic states, identify the P-indices, drug exposures, and dosing intervals of each drug that PD-optimizes the rapidity and extent of killing of DS-Mtb in each of the 3 metabolic states. Determine if these single drug regimens can prevent resistance. Specific Aim #2. With the HFIM, compare the rates and extents of killing of DS-Mtb in the 3 metabolic states and the effect of these antibiotics on the less susceptible Mtb population when the PD-optimized regimens developed in Specific Aim #1 are used as 2 and 3 drug combinations. Employ innovative mathematical models to identify the dose and frequency of administration of each antibiotic in a 3 drug regimen that is predicted to provide a shorter course, highly effective regimen for the treatment of human TB by optimizing the killing of Mtb in each metabolic state and by preventing resistance. Specific Aim #3. Using the HFIM, characterize the efficacy of the PD-optimized 3 drug regimen on the rate and extent of killing of Mtb in 3 metabolic states for strains that are resistant to 1 of the drug components. Specific Aim #4. Prospectively validate the performance of the innovative PD-optimized 3 drug regimen in a novel murine model of pulmonary TB in which Mtb in log phase, acidic phase, and NRP state co-exist and in another innovative in vivo model of TB using state-of-the-art dosing algorithms that "humanize" the PK profiles generated in the animals. Use the novel murine model to characterize the relative efficacy of this regimen for the killing of DS- and MDR-TB.