Gut Microbiome and Pharmacokinetic Variability in Tuberculosis and Diabetes

项目概要/摘要 在了解低药物依赖的机制和生物学预测因子方面存在重大的知识缺口。 结核病（TB）和2型糖尿病（DM）患者的暴露和治疗失败。解决 糖尿病对结核病预后不良的影响，我们提出了一个跨学科的指导研究和培训计划， 研究肠道微生物群介导DM和非DM TB中抗TB药物药代动力学（PK）变化 一项正在进行的前瞻性、观察性PK试验中的患者，研究异烟肼、利福平和吡嗪酰胺在 肺结核病人。具体目标1将量化DM和肠道微生物群α多样性对糖尿病的影响。 口服抗结核药物在治疗活动性结核病患者中的生物利用度， 与糖尿病和措施的肠道菌群失调的活动性结核病患者和无糖尿病。具体目标2将 描述活动性结核病患者肠道微生物群α多样性与糖尿病的关系， 通过对来自临床粪便标本的人类肠道微生物组进行全面的前瞻性分析。 在成功完成拟议的K23研究后，我们希望我们的贡献是：1）建立 以前未描述的人类肠道微生物组的影响作为一个重要的协变量来解释 接受活动性TB治疗的患者中药物PK的异质性，2）证明了 结核病患者中DM和肠道微生物组多样性和组成之间的关系。这些贡献将是 重要的是，因为他们预计将提供强有力的科学理由的新机制， TB/DM患者中抗TB药物PK和TB治疗反应的先前无法解释的变异性。 这项研究具有创新性，因为它旨在将肠道微生物组确定为一种新机制 这是抗结核药物PK异质性的基础。这个K23提案的总体目标是训练纳瓦尼斯 纳拉亚南，药学博士，公共卫生硕士的职业生涯作为一个独立的研究者在药物微生物学，研究 微生物组变异通过调节药物PK和药效学（PD）对治疗反应的影响， 职业重点是结核病和其他传染病的治疗和结果。职业 发展计划包括在马丁·布拉泽博士的指导下进行人类微生物组研究的培训， 和药物计量学，定量临床药理学和系统生物学的跨学科科学， 涉及数学建模方面的专业知识，以表征和预测药物PK和PD。纳拉亚南博士将 此外，他还接受了国际抗结核药理学和结核病临床研究专家Scott Heysell博士的指导。 拟议的K23项目将提供一个综合计划，指导以病人为导向的研究，职业生涯， 开发活动和微生物组研究和药物计量学方面的正式培训。专家指导 导师和合作者，研究和培训活动概述了本申请将使博士。 Narayanan将成长为一名独立的临床/翻译研究人员。这些机会将装备这一 具有更多技能的调查员，能够回答有关全球传染病的重要和新问题。

PROJECT SUMMARY/ABSTRACT There are significant knowledge gaps in understanding the mechanisms and biological predictors of low drug exposures and treatment failure in patients with tuberculosis (TB) and type 2 diabetes mellitus (DM). To address the impact of DM on poor TB outcomes, we propose an interdisciplinary mentored research and training plan to investigate gut microbiome-mediated variation of anti-TB drug pharmacokinetics (PK) in DM and non-DM TB patients in an ongoing prospective, observational PK trial investigating isoniazid, rifampin, and pyrazinamide in TB patients. Specific Aim 1 will quantify the effect of DM and gut microbiota alpha diversity on the bioavailability of oral anti-TB drugs in patients treated for active TB, by linking pharmacometric modeling with DM and measures of the gut dysbiosis in active TB patients with and without DM. Specific Aim 2 will characterize the relationship of gut microbiota alpha diversity and diabetes in patients with active TB, by conducting a comprehensive prospective analysis of the human gut microbiome from clinical stool specimens. Upon successful completion of the proposed K23 research, we expect our contribution to 1) establish the previously undescribed impact of the human gut microbiome as a significant covariate to explain the heterogeneity of drug PK in patients receiving active TB treatment and, 2) demonstrate the distinctive relationship between DM and gut microbiome diversity and composition among patients with TB. These contributions will be significant because they are expected to provide strong scientific justification for a novel mechanism for the previously unexplained variability of anti-TB drug PK and TB treatment response among patients with TB/DM. The proposed research is innovative because it aims to identify the gut microbiome as a novel mechanism underlying the heterogeneity of anti-TB drug PK. The overall goal of this K23 proposal is to train Navaneeth Narayanan, PharmD, MPH for a career as an independent investigator in pharmacomicrobiomics, the study of the effect of microbiome variation on therapeutic response by regulating drug PK and pharmacodynamics (PD), with a specific career emphasis on the treatment and outcomes of TB and other infectious diseases. The career development plan includes training in human microbiome research, under the mentorship of Dr. Martin Blaser, and pharmacometrics, an interdisciplinary science of quantitative clinical pharmacology and systems biology that involves expertise in mathematical modeling to characterize and predict drug PK and PD. Dr. Narayanan will also be mentored by Dr. Scott Heysell, an international expert in anti-TB pharmacology and TB clinical research. The proposed K23 project will provide an integrated plan of mentored patient-oriented research, career development activities, and formal training in microbiome research and pharmacometrics. Guided by expert mentors and collaborators, the research and training activities outlined in this application will enable Dr. Narayanan to mature into an independent clinical/translational researcher. These opportunities will equip this investigator with a larger set of skills to answer important and novel questions about global infectious diseases.