A Clinical Pharmacology Study of a Novel Drug Regimen for Pre XDR and XDR Tuberculosis

 描述(申请人提供)：全球出现耐多药结核病(MDR-TB)是一个巨大的公共卫生威胁和有效控制结核病的障碍。鉴于相关的高死亡率和糟糕的治疗结果，导致前期广泛耐药(XDR)和广泛耐药结核病的进一步耐药性的增加尤其令人震惊，特别是与药物敏感、甚至是耐多药结核病相比。最近推出的重新调整用途和新发现的药物为改善广泛耐药前和广泛耐药结核病的治疗结果提供了希望，但关键的知识差距仍然存在。在广泛耐药结核病患者中，关于重新使用的药物和新药联合使用时的性能、获得性耐药率以及新药方案的药代动力学和药效学(PK/PD)的数据很少。结核病药物PK/PD的重要性最近在对药物敏感的结核病患者中的研究中得到了强调；然而，在患有广泛耐药前和广泛耐药结核病的患者中，新药组合是否如此尚不清楚。重新调整用途和新的结核病药物渗透到肺部的能力也是未知的，这将是设计有效方案时的重要信息。我们提出了一项前瞻性的观察性研究，以评估新型结核病药物方案的PK/PD，包括它们对来自格鲁吉亚的肺前XDR和XDR-TB患者的空洞渗透。我们假设，最佳的药物浓度将与培养转化的时间更快和获得性耐药性较低相关。更好地了解新药方案的临床药理学将有助于确保最佳和负责任地使用新药组合，从而改善广泛耐药前和广泛耐药结核病的治疗。这项建议的具体目的包括：1)测定新药[贝达奎林(BDQ)、利奈唑胺(LNZ)和氯法齐明(CFZ)]在肺部耐药前和广泛耐药结核患者中的血清药代动力学。我们将在格鲁吉亚第比利斯的国家结核病和肺部疾病中心招募60名接受这种新型药物组合的患者。将进行PK建模以确定最佳血清药物浓度的预测因子。2)探讨BDQ、LNZ和CFZ的血清药代动力学与临床转归的关系。在治疗3-6周时进行密集的PK采样和MIC检测。我们将利用全基因组测序(WGS)来评估抗性的遗传决定因素。我们的结果将为新引入的药物方案的最佳浓度提供新的数据，以及关于毒性和药物-药物相互作用的重要信息。3)研究BDQ、LNZ和CFZ在接受辅助手术治疗的前XDR和XDR-TB患者中的组织药代动力学。利用10名患者的新队列和创新的微透析技术，我们将提供有关空洞穿透以及空洞是否为这些新引入的药物的AR部位的第一批数据。

 DESCRIPTION (provided by applicant): The global emergence of multidrug-resistant tuberculosis (MDR-TB) is an enormous public health threat and barrier to effective TB control. The rise in further drug resistance leading to pre-extensively drug-resistant (XDR) and XDR-TB is particularly alarming given the associated high mortality and poor treatment outcomes, especially compared to drug susceptible and even MDR-TB. The recent introduction of repurposed and newly discovered drugs offers promise in improving pre-XDR and XDR-TB treatment outcomes but critical knowledge gaps exist. There are scarce data on the performance of repurposed and novel drugs when used in combination, among patients with XDR-TB, rates of acquired drug resistance, and the pharmacokinetics and pharmacodynamics (PK/PD) of new drug regimens. The importance of TB drug PK/PD has recently been emphasized by studies among patients with drug susceptible TB; however, whether this is the case for new drug combinations among patients with pre-XDR and XDR-TB is unknown. The ability of repurposed and novel TB drugs to penetrate into the lung, the main site of disease, is also undetermined and will be vital information when designing effective regimens. We propose a prospective observational study to evaluate the PK/PD of novel TB drug regimens, including their cavitary penetration, among patients with pulmonary pre-XDR and XDR-TB from the country of Georgia. We hypothesize that optimal drug concentrations will be associated with a faster time to culture conversion and less acquired drug resistance. A better understanding of the clinical pharmacology of new drug regimens will help ensure optimal and responsible use of new drug combinations and thus improve pre-XDR and XDR-TB treatment. The Specific AIMs of this proposal include: 1) To determine the serum pharmacokinetics of newly introduced drugs [bedaquiline (BDQ), linezolid (LNZ), and clofazimine (CFZ)] among patients with pulmonary pre-XDR and XDR-TB. We will enroll 60 patients receiving this novel drug combination at the National Center for TB and Lung Diseases in Tbilisi, Georgia. PK modeling will be performed to identify predictors of optimal serum drug concentrations. 2) To investigate the association of BDQ, LNZ and CFZ serum pharmacokinetics with clinical outcomes among patients with pre-XDR and XDR-TB in AIM 1. Intensive PK sampling will be performed at 3-6 weeks of treatment along with MIC testing of positive cultures. We will utilize whole genome sequencing (WGS) to assess genetic determinants of resistance. Our results will provide novel data on the optimal concentrations of newly introduced drug regimens as well as vital information on toxicities, and drug-drug interactions. 3) To determine the tissue pharmacokinetics of BDQ, LNZ, and CFZ in tuberculous cavitary lung among patients with pre-XDR and XDR-TB undergoing adjunctive surgical therapy. Utilizing a new cohort of 10 patients and an innovative technique of microdialysis, we will provide the first data on cavitary penetration and whether the cavity is a site of AR to these newly introduced drugs.