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（由适用提供）：耐多药结核病（MDR-TB）的全球出现是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不良的治疗结果，尤其是与药物易感性甚至MDR-TB相比，导致预耐药（XDR）和XDR-TB的进一步耐药性的上升尤其令人震惊。最近引入的重新定位和新发现的药物在改善XDR和XDR-TB治疗结果方面提供了希望，但存在关键的知识差距。在组合使用XDR-TB的患者，获得的药物耐药率以及新药方案的药代动力学和药效学（PK/PD）的患者中，在组合组合中使用了重新利用和新型药物的性能的稀缺数据。最近，药物易感性结核病患者的研究强调了结核病药物PK/PD的重要性。但是，尚不清楚XDR和XDR-TB患者的新药组合是这种情况。重新利用和新型结核病药物渗透到肺部的主要部位的能力也尚不确定，在设计有效方案时将是至关重要的信息。我们提出了一项前瞻性观察性研究，以评估来自佐治亚州肺前XDR和XDR-TB患者的新型结核病药物治疗方案的PK/PD，包括它们的咖啡馆穿透。我们假设最佳药物浓度将与更快的培养时间转化和耐药性较低的时间有关。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的新药组合使用，从而改善XDR和XDR-TB治疗。该提案的具体目的包括：1）确定新引入的药物的血清药代动力学[Bedaquiline（BDQ），LineZolid（LNZ）和Clofazimine（CFZ）]患有肺部前XDR和XDR-TB的患者中。我们将在佐治亚州第比利斯国家的国家结核病和肺部疾病中心接受60名接受这种新药物组合的患者。将进行PK建模以识别最佳血清药物浓度的预测指标。 2）研究BDQ，LNZ和CFZ血清药代动力学与AIM 1中XDR和XDR-TB患者的临床结局的关联。在3-6周的治疗中将进行密集的PK采样以及MIC测试阳性培养物。我们将利用整个基因组测序（WGS）评估抗药性的遗传决定剂。我们的结果将提供有关新引入药物方案的最佳浓度以及有关毒性和药物相互作用的重要信息的新数据。 3）确定在进行辅助手术疗法的前XDR和XDR-TB患者中，在结核病的腔肺中，BDQ，LNZ和CFZ的组织药代动力学。利用新的10名患者组成的新队列和一种微透析的创新技术，我们将提供有关腔体穿透性的第一个数据，以及腔是否是AR的位置，是否是这些新引入的药物。