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

治疗 XDR 前和 XDR 结核病的新药物方案的临床药理学研究

• 批准号: 9207096
• 负责人: Russell Ryan Kempker
• 金额: $ 19.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207096
• 关键词: Acquired Immunodeficiency Syndrome; Cessation of life; Clinical; Clinical Pharmacology; Country; DNA Sequence Alteration; Data; Development; Diabetes Mellitus; Disease; Drug Interactions; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Enrollment; Ensure; Epidemic; Extreme drug resistant tuberculosis; FDA approved; Funding; Future; Genetic Determinism; Genomics; HIV; Hepatitis C; Knowledge; Linezolid; Lung; Lung diseases; Malaria; Measures; Microdialysis; Modeling; Molecular; Multidrug-Resistant Tuberculosis; National Institute of Allergy and Infectious Disease; Observational Study; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Prevalence; Public Health; Regimen; Research; Research Priority; Resistance; Sampling; Serum; Site; Sputum; Techniques; Testing; Time; Tissues; Toxic effect; Translational Research; Treatment outcome; Tuberculosis; United States National Institutes of Health; World Health Organization; acquired drug resistance; cohort; design; drug testing; extensive drug resistance; fighting; genome sequencing; improved; innovation; mortality; novel; novel drug combination; novel therapeutics; prospective; public health relevance; research study; resistance mechanism; tuberculosis drugs; tuberculosis treatment; whole genome

 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.

 描述（由申请人提供）：全球出现的耐多药结核病（MDR-TB）对公共卫生构成了巨大威胁，也是有效结核病控制的障碍。耐药性的进一步上升导致了广泛耐药（XDR）。考虑到广泛耐药结核病的相关高死亡率和不良治疗结果，特别是与药物敏感甚至耐多药结核病相比，最近引入的重新用途和新发现的药物为改善广泛耐药结核病前和严重耐药结核病提供了希望。广泛耐药结核病的治疗结果，但存在关键的知识差距，关于联合使用时的新药和新药的性能、广泛耐药结核病患者、获得性耐药率以及药代动力学和药效学（PK/PD）的数据很少。最近针对药物敏感结核病患者的研究强调了结核病药物 PK/PD 的重要性，但尚不清楚新药组合在前广泛耐药结核病和广泛耐药结核病患者中的情况是否如此。 .能力改变用途的新型结核病药物渗透到肺部（疾病的主要部位）的情况也尚未确定，这将是设计有效治疗方案时的重要信息，我们提出一项前瞻性观察性研究来评估新型结核病药物治疗方案的 PK/PD，包括。在来自乔治亚州的患有前 XDR 和 XDR-TB 的患者中，我们追求最佳的药物浓度与更快的文化转化时间和更少的获得性耐药性相关。的新药物治疗方案将有助于最佳地确保和负责任地使用新药物组合，从而改善 XDR 前和 XDR-TB 治疗。该提案的具体目标包括： 1) 确定新引入药物 [bedaquiline (BDQ) 的血清药代动力学。 、利奈唑胺 (LNZ) 和氯法齐明 (CFZ)] 在肺前 XDR 和 XDR-TB 患者中的应用 我们将在国家结核病中心招募 60 名接受这种新型药物组合的患者。将在格鲁吉亚第比利斯进行肺部疾病建模，以确定最佳血清药物浓度的预测因子 2) 研究 BDQ、LNZ 和 CFZ 血清药代动力学与 AIM 前 XDR 和 XDR-TB 患者的临床结果之间的关系。 1. 治疗后 3-6 周将进行密集 PK 采样，并对阳性培养物进行 MIC 检测，我们将利用全基因组测序 (WGS) 来评估耐药性的遗传决定因素。提供有关新引入药物方案的最佳浓度的新数据以及有关毒性和药物相互作用的重要信息 3) 确定 BDQ、LNZ 和 CFZ 在 XDR 患者的结核性空洞肺中的组织药代动力学。利用由 10 名患者组成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是结核病部位的第一批数据。 AR 对这些新推出的药物。