PK-PD of combination antituberculosis therapy for suppression of drug-resistance

描述（由申请人提供）：结核病（TB）是有史以来最重要的杀手之一。一线治疗包括利福平、异烟肼和吡嗪酰胺的联合治疗，受到耐多药结核病和广泛耐药结核病发展的威胁。耐药性在很大程度上是由于依从性差造成的。据推测，耐药的产生是由于成分药物的药代动力学不匹配、酸性和缺氧条件下杆菌的有效单一治疗、药物的不同抗生素后效应以及突变选择窗口（TMSW）的延长。我们将使用药代动力学-药效学（PK-PD）方法检验这些假设。我们已经开发了一种体外PKPD结核病模型，我们已经用它来研究在杀菌活性期间对利福平和异烟肼单药治疗的耐药性出现。迄今为止，尚未对灭菌过程中出现的PK-PD抗性进行研究。在目前的应用中，我们提供了pyrazinamide灭菌活性的PK-PD数据，为研究联合抗结核药物的杀菌和灭菌活性的PK-PD奠定了基础。我们的长期目标是制定抗结核治疗剂量策略，从而抑制耐多药结核病。当前应用的目的是使用体外结核PK-PD模型，使结核分枝杆菌暴露于与人类相似的抗结核药物药代动力学中。我们的中心假设是PK-PD联合抗结核方案的优化将导致耐多药结核病的抑制。我们将检验假设，并通过检查四个具体目标来实现我们的目标。(1)我们将应用PK-PD方法来检验药代动力学错配-、有效单药治疗-和TMSW-假说。(2)我们将确定一线抗结核药物联合治疗在杀菌和灭菌治疗期间与抑制耐药性相关的暴露。(3)我们将确定与耐药性出现相关的不良依从性程度，并确定PK-PD解决方案，以减少耐多药结核病的出现，尽管依从性较差。我们还将确定染色体突变的出现顺序，这些突变在不遵医嘱期间赋予耐药性。(4)我们将通过蒙特卡罗模拟来解释体外PK-PD暴露和抑制人类治疗耐药性的策略。我们将在体外模型中检查2药和3药组合在杀菌和灭菌活性期间的情况，并检查每种特定给药策略下产生的耐药亚群的大小。我们的体外模型使用毒性结核分枝杆菌，并模拟结核病患者遇到的药物的浓度-时间分布。从拟议的研究来看，我们预计一些关于耐药性如何产生的标准解释是错误的，这将导致减少耐多药结核病战略的根本改变。由于依从性差是临床生活的一个事实，在依从性差的情况下抑制耐药性的给药策略将是一项重大的治疗创新。结核病是一个全球性问题，已被国际社会宣布为全球性问题。一个特别大的问题是耐多药结核病的出现。目前的应用将采用药代动力学-药效学解决方案来解决这一公共卫生问题。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is one of the most important killers of all time. First-line therapy, which consists of combination of rifampin, isoniazid, and pyrazinamide, is under threat from the development of multi-drug resistant TB (MDR-TB) and extensively drug resistant TB. The drug resistance is driven, to a great extent, by poor compliance. It is hypothesized that resistance emerges due to the pharmacokinetic mismatch of component drugs, effective monotherapy of bacilli under acidic and hypoxic conditions, differential post-antibiotic effects of drugs, and prolonged time in the mutant selection window (TMSW). We will test these hypotheses using pharmacokinetic-pharmacodynamic (PK-PD) methods. We have developed an in vitro PKPD model of TB which we have used to study resistance emergence to rifampin and isoniazid monotherapy during bactericidal activity. PK-PD studies of resistance emergence during sterilizing activity had as of yet not been performed. In the current application, we present PK-PD data on pyrazinamide sterilizing activity, setting the stage to study the PK-PD of combination anti-TB drugs during both bactericidal and sterilizing activity. Our long term goal is to develop anti-TB therapy dosing strategies that will lead to suppression of MDR-TB. The objective of the current application is to use the in vitro PK-PD model of TB to expose Mycobacterium tuberculosis to anti-TB drug pharmacokinetics similar to those encountered in humans. Our central hypothesis is that PK-PD optimization of combination anti-TB regimens will lead suppression of MDR-TB. We will test the hypothesis and achieve our objectives by examining four specific aims. (1) We will apply PK-PD methods to test the pharmacokinetic mismatch-, the effective monotherapy-, and the TMSW- hypothesis. (2) We will identify the exposures of first line anti-TB drug combination therapy that are associated with suppression of resistance during both bactericidal and sterilizing therapy. (3) We will identify the degree of poor compliance associated with emergence of resistance and identify PK-PD solutions to reduce emergence of MDR-TB, despite the poor compliance. We will also identify the order of emergence of chromosomal mutations that confer drug resistance during non-compliance. (4) We will translate the in vitro PK-PD exposures and strategies that suppress resistance to human therapy by use of Monte Carlo simulations. We will examine 2-drug and 3-drug combinations during both bactericidal and sterilizing activity in the in vitro model, and examine the size of resistant sub-populations that arise with each particular dosing strategy. Our in vitro model uses virulent M. tuberculosis and mimics the concentration-time profile of drugs encountered in TB patients. From the proposed studies, we expect some of the standard explanations on how resistance arises to be false, which will lead to fundamental changes in strategies to reduce MDR-TB. Since poor compliance is a fact of clinical life, dosing strategies that suppress drug resistance despite poor compliance would be a major therapeutic innovation. Tuberculosis is a global problem that has been declared a global emergence by the international community. A particularly big problem is the emergence of multidrug resistant tuberculosis. The current application will apply pharmacokinetic-pharmacodynamic solutions to this public health problem.