Short course therapy for MDR-TB based on PK/PD answers for biological variability

描述(申请人提供)：耐药结核病(TB)，特别是耐多药结核病(MDR-TB)，是一个主要的公共卫生威胁。耐多药结核病的流行正在增加，包括最近的报告表明，一些结核病病例现在对所有已知的抗结核药物都具有耐药性。耐多药结核病的治疗不如对药物敏感的结核病有效，与更严重的药物毒性有关，更昂贵，对于注射药物需要住院。儿童耐多药结核病与成人结核病有很大不同，因此对儿童耐多药结核病的治疗，即使有的话，特点也很差。本课题组使用结核的中空纤维系统模型(HFS)表明，获得性耐药(ADR)和治疗失败的主要原因之一是患者之间的药物代谢差异。在一些快速和差异化代谢某些药物的患者中，会产生一种情况，即他们有效地处于一种有效的单一药物之下，这导致了ADR。ADR的另一个原因是一些结核分枝杆菌(Mtb)谱系已被证明是高度可变的。在耐多药结核病的治疗中，第三个问题是药物的高毒性，导致治疗的完成性较差。我们成功地用三维人体器官型肝脏和皮肤组织改装了HFS，这样就可以在检测药物毒性的同时检测治疗耐多药结核病的方案的疗效。此外，我们还设计了一种与儿童播散性细胞内疾病相关的HFS。我们的目标是设计一种由以下药物组成的抗结核病方案：(A)非专利药物，(B)廉价，(C)容易获得，(D)可以口服，在 HFS将对不同的结核分枝杆菌血统有效。疗效结果将通过以下方式进行验证 两种小鼠模型，药物药代动力学与人类成人和儿童相似。我们还将研究测量药物浓度，然后进行迭代干预，个体化给药，以提高疗效，减少不良反应，减少毒性，同时在资源匮乏的情况下仍具有成本效益。我们将通过在德克萨斯大学西南医学中心甘博博士的实验室进行一系列HFS疗效、ADR和毒性试验来实现我们的目标。接下来，我们将基于约翰霍普金斯医学中心Eric Nuermberger博士实验室的人性化药代动力学，在两个小鼠模型中验证最佳药物方案，一个用于成人肺结核病，另一个用于播散性结核病。用选定的药物治疗对不同结核分枝杆菌谱系的突变率的影响将在哈佛大学的萨拉·福琼博士的实验室进行测量。结果将被用于计算机辅助临床模拟，以便将给药策略翻译给患者。

DESCRIPTION (provided by applicant): Drug resistant tuberculosis (TB), especially multi-drug resistant TB (MDR-TB), is a major public health threat. The prevalence of MDR-TB is increasing, including recent reports that indicate that some cases of TB are now resistant to all known anti-TB drugs. Treatment of MDR-TB is less effective than for drug susceptible TB, is associated with more severe drug toxicities, is more expensive, and for injectable drugs requires hospitalization. Treatment of MDR-TB in children, in whom TB disease is very different from that in adults, is poorly characterized, if at all. Our group has used the hollow fiber system model of TB (HFS) to show that one of the main reasons for acquired drug resistance (ADR) and therapy failure is the between-patient differences in drug metabolism. In some patients who rapidly and differentially metabolize some drugs, there is created a situation whereby they are effectively under a single drug that is effective, which leads to ADR. Another reason for ADR is that some Mycobacterium tuberculosis (Mtb) lineages have been shown to be hypermutable. In treatment of MDR-TB, a third problem is the high toxicity of drugs, leading to poor completion of therapy. We successfully retrofitted the HFS with 3-dimensional human organotypic liver and skin tissue, so that drug toxicities can be examined at the same time we examine efficacy of regimens against MDR-TB. In addition, we have designed a HFS that is relevant to disseminated intracellular disease in children. Our aim is to design an anti-TB regimen comprising of drugs that are (a) off-patent, (b) cheap, (c) readily available, and (d) can be administered by mouth, in the HFS that will be effective for different Mtb lineages. Efficacy results will be validated using two mouse models, with drug pharmacokinetics similar to those in human adults and children. We will also investigate measuring drug concentrations followed by an iterative intervention with individualized dosing to improve efficacy, reduce ADR, and reduce toxicity, while still being cost-effective in resource poor settings. We will attain our goals by performing a series of HFS experiments for efficacy, ADR, and toxicity in Dr. Gumbo's laboratory at UT Southwestern Medical Center. Next, we will validate the optimal drug regimens in two mouse models, one for adult pulmonary TB and the other for disseminated TB, based on humanized pharmacokinetics in Dr. Eric Nuermberger's laboratory at Johns Hopkins Medical Center. The effects of treatment with chosen drugs on mutation rates of different Mtb lineages will be measured in Dr. Sarah Fortune's lab at Harvard. Results will be employed in computer aided clinical simulations in order to translate dosing strategies to patients.