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

描述（由申请人提供）：耐药结核病（TB），特别是耐多药结核病（MDR-TB），是一种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具有耐药性。耐多药结核病的治疗效果不如药物敏感结核病，与更严重的药物毒性相关，费用更高，而且注射药物需要住院治疗。儿童的耐多药结核病与成人的结核病有很大的不同，即使有治疗，儿童耐多药结核病的特点也很差。本课组利用TB （HFS）的中空纤维系统模型表明，获得性耐药（ADR）和治疗失败的主要原因之一是患者之间药物代谢的差异。对于一些快速代谢不同药物的患者，会产生一种情况，即他们在一种有效的药物下有效，这就导致了ADR。不良反应的另一个原因是，一些结核分枝杆菌（Mtb）谱系已被证明是超可变的。在耐多药结核病的治疗中，第三个问题是药物的高毒性，导致治疗完成度低。我们成功地用三维人体器官型肝脏和皮肤组织改造了HFS，这样我们就可以在检查耐多药结核病方案疗效的同时检查药物毒性。此外，我们还设计了一个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抗结核方案，其中包括(a)非专利药物、(b)廉价药物、(c)现成药物和(d)可口服药物

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.