Gut Microbiome and Pharmacokinetic Variability in Tuberculosis and Diabetes

结核病和糖尿病的肠道微生物组和药代动力学变异

• 批准号: 10371554
• 负责人: Navaneeth Narayanan
• 金额: $ 19.94万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371554
• 关键词: Active Learning; Address; Antitubercular Agents; Bacteria; Bioinformatics; Biological; Biological Availability; Biological Markers; Butyrates; Cause of Death; Cessation of life; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Research; Communicable Diseases; Complex; Data; Development Plans; Diabetes Mellitus; Doctor of Pharmacy; Drug Exposure; Drug Kinetics; Future; Goals; Grant; Heterogeneity; Human; Human Microbiome; Infrastructure; International; Knowledge; Lead; Link; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic Diseases; Methodology; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Population; Pyrazinamide; Regimen; Relapse; Research; Research Activity; Research Design; Research Personnel; Research Training; Rifampin; Sampling; Science; Secure; Sputum; Statistical Data Interpretation; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Training Activity; Treatment Failure; Treatment outcome; Tuberculosis; Variant; absorption; antimicrobial; bacterial metabolism; career; career development; clinical care; comorbidity; drug disposition; drug efficacy; drug metabolism; dysbiosis; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; improved; innovation; insight; interest; isoniazid; mathematical model; microbial; microbial community; microbiome; microbiome research; microbiome signature; novel; novel strategies; patient oriented research; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacometrics; prevent; programs; prospective; research and development; skills; stool sample; targeted treatment; therapeutic target; therapy design; therapy resistant; translational scientist; treatment response; treatment risk; tuberculosis drugs; tuberculosis treatment

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.

项目摘要/摘要 在理解低药物的机制和生物学预测因子方面存在很大的知识差距 结核病患者（TB）和2型糖尿病（DM）的暴露和治疗失败。解决 DM对结核病结果差的影响，我们建议跨学科的指导研究和培训计划 研究肠道微生物组介导的DM和非DM TB中抗TB药代动力学（PK）的变化 正在进行的前瞻性，观察性PK试验中，正在研究异念珠菌，利福平和吡嗪酰胺的患者 结核病患者。具体目标1将量化DM和肠道微生物α多样性对 通过连接药物计量模型的患者口服抗TB药物的生物利用度 在有或没有DM的活性结核病患者中，DM和肠道断疾病的测量值。具体目标2将 表征活性结核病患者的肠道菌群多样性和糖尿病的关系 通过对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。 成功完成拟议的K23研究后，我们希望我们对1）建立贡献 以前人类肠道微生物组的未描述的影响是一个重要的协变量来解释 药物PK在接受活性结核病治疗的患者中的异质性，2）证明了独特的关系 TB患者的DM和肠道微生物组的多样性和组成之间。这些贡献将是 意义重大，因为他们有望为新的机制提供强有力的科学理由 TB/DM患者中抗TB药物PK和结核病治疗反应的以前无法解释的变异性。 拟议的研究具有创新性，因为它旨在将肠道微生物组识别为一种新型机制 抗TB药物PK的异质性的基础。该K23提案的总体目标是培训Navaneeth 纳拉亚南（Narayanan 通过调节药物PK和药效学（PD），微生物组变异对治疗反应的影响， 特别强调结核病和其他传染病的治疗和结果。职业 发展计划包括在Martin Blaser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，一门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。 Narayanan博士Will 也由抗结核药理学和结核病临床研究的国际专家Scott Heysell博士指导。 拟议的K23项目将提供一个综合的计划，以指导患者的研究，职业 开发活动以及微生物组研究和药物计量学方面的正式培训。由专家指导 导师和合作者，本申请中概述的研究和培训活动将使博士 Narayanan成为独立的临床/翻译研究人员。这些机会将为这个 研究人员具有更大的技能，可以回答有关全球传染病的重要问题。