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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要在了解低药物的机制和生物学预测因素方面存在重大知识差距结核病 (TB) 和 2 型糖尿病 (DM) 患者的暴露和治疗失败。致地址为了了解 DM 对结核病不良结果的影响，我们提出了一项跨学科指导的研究和培训计划，以研究 DM 和非 DM TB 中肠道微生物介导的抗结核药物药代动力学 (PK) 的变化一项正在进行的前瞻性、观察性 PK 试验中的患者，该试验调查异烟肼、利福平和吡嗪酰胺在结核病患者。具体目标 1 将量化 DM 和肠道微生物群 α 多样性对通过联系药理学模型，了解口服抗结核药物在活动性结核病治疗患者中的生物利用度糖尿病以及患有和不患有糖尿病的活动性结核病患者肠道菌群失调的测量。具体目标 2 将表征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，通过对临床粪便标本中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，我们期望做出贡献：1) 建立先前未描述的人类肠道微生物组的影响作为解释这一现象的重要协变量接受积极结核病治疗的患者中药物 PK 的异质性，2) 证明了独特的关系糖尿病与结核病患者肠道微生物组多样性和组成之间的关系。这些贡献将意义重大，因为它们有望为一种新颖的机制提供强有力的科学依据。 TB/DM 患者中抗结核药物 PK 和结核治疗反应的先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机制抗结核药物PK异质性的潜在原因。这个 K23 提案的总体目标是训练 Navaneeth Narayanan，药学博士，公共卫生硕士，作为药物微生物组学的独立研究者，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，其职业重点是结核病和其他传染病的治疗和结果。职业生涯发展计划包括在 Martin Blaser 博士的指导下进行人类微生物组研究培训，和药理学，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来表征和预测药物 PK 和 PD。纳拉亚南博士将并得到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 项目将提供一个以患者为导向的研究、职业指导的综合计划开发活动以及微生物组研究和药理学方面的正式培训。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。纳拉亚南 (Narayanan) 成长为一名独立的临床/转化研究员。这些机会将装备这个具有更多技能的调查员可以回答有关全球传染病的重要和新颖的问题。