Optimizing Anti-mycobacterial Therapy Using A Pharmacology-based Approach

使用基于药理学的方法优化抗分枝杆菌治疗

• 批准号: 10540813
• 负责人: Elisa Helen Ignatius
• 金额: $ 19.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540813
• 关键词: Adverse event; Advisory Committees; Antibiotics; Antimycobacterial Agents; Area; Azithromycin; Bronchiectasis; Cessation of life; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Trials; Collaborations; Colony-forming units; Combined Antibiotics; Combined Modality Therapy; Committee Members; Communicable Diseases; Companions; Complex; Country; Data; Development; Disease; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug resistance; Drug toxicity; Drug usage; Enzymes; Evaluation; Funding; Future; Goals; Hepatotoxicity; Immune response; Incidence; Institution; Investigation; Kinetics; Knowledge; Lead; Learning; Licensing; Lung; Lung diseases; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Modeling; Mycobacterium Infections; Mycobacterium avium Complex; New Agents; Nitroimidazoles; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Physicians; Population; Positioning Attribute; Pravastatin; Pre-Clinical Model; Research; Research Personnel; Resources; Rifabutin; Rifampin; Science; Scientist; Serum; Sputum; Therapeutic; Time; Toxic effect; Training; Tuberculosis; Writing; analytical method; bactericide; design; drug biological activity; drug development; drug-sensitive; high risk; improved; in vivo; lung injury; minimal inhibitory concentration; multidisciplinary; mycobacterial; non-tuberculosis mycobacteria; novel; novel therapeutics; pharmacokinetic model; pharmacologic; pharmacometrics; predictive tools; response; screening; skill acquisition; skills; standard care; standard of care; success; tool; treatment effect; trial design; trial enrollment; tuberculosis drugs; tuberculosis treatment

Project Summary/Abstract The global burden of mycobacterial infections remains staggering, with over 10 million new tuberculosis (TB) cases and 1.2 million deaths in 2019, and a recent rising incidence of nontuberculous mycobacteria (NTM). Treatment of both TB and NTM is hindered by the need for prolonged combination antibiotics, drug resistance, toxicity, drug-drug interactions and sub-optimal efficacy. After decades without many new agents, there are now concerted efforts to identify and integrate novel drugs, optimize existing drugs, and augment host immune response. Clinical pharmacology, when integrated throughout drug development, defines critical relationships between drug exposure and effect (or toxicity), identifies key interactions, and enhances treatment success. However, to date, there is a dearth of physician scientists with dual training in infectious diseases and clinical pharmacology who can champion these drug development efforts, especially for NTM. In this proposal, the candidate will apply clinical pharmacology tools to the problem of mycobacterial therapeutics and utilize the resources and framework of three funded clinical trials that are being led by mentors and advisory committee members. Backed by a strong multidisciplinary advisory team with expertise in clinical pharmacology, mycobacterial drug development, pharmacometrics, and mycobacteriology, the candidate will 1) define the pharmacokinetics-pharmacodynamics (PK-PD) of azithromycin for Mycobacterium avium complex (MAC) lung disease by applying the early bactericidal activity (EBA) trial design (Aim 1); 2) identify predictors of toxicity for a novel nitroimidazole antibiotic using PK-toxicodynamic (PK-TD) modeling (Aim 2); and 3) determine the magnitude of drug-drug interaction (DDI) between first-line TB treatment and pravastatin as host-directed therapy (Aim 3). Each one of these aims will provide an opportunity to not only learn but also implement pharmacologic analytical methods for the investigation of both TB and NTM. The candidate will gain skills including population PK modeling, execution of early bactericidal activity trial design, PK-toxicodynamic modeling, and development of a clinical toxicity prediction tool. This K23 Mentored Patient-Oriented Research Career Development Award will serve not only to advance research in mycobacterial therapeutics, but also support the candidate to gain the skills necessary to perform fundamental and advanced clinical pharmacology analyses, lead clinical trials, and form strong multi- institutional collaborations. Upon completion of this K23, the candidate will be well positioned as an independent clinical investigator with expertise in infectious diseases, applied antimycobacterial pharmacology, and NTM therapeutics.

项目总结/摘要 分枝杆菌感染的全球负担仍然令人震惊，有超过1000万新的结核病（TB） 2019年有120万例病例和120万例死亡，最近非结核分枝杆菌（NTM）的发病率也在上升。 结核病和非结核病的治疗受到需要长期联合抗生素、耐药性、 毒性、药物间相互作用和次优疗效。在几十年没有新的代理人之后， 现在，我们共同努力，鉴定和整合新药，优化现有药物，并增强宿主免疫力， 反应临床药理学，当整合在整个药物开发，定义关键关系 在药物暴露和效应（或毒性）之间，确定关键的相互作用，并提高治疗成功率。 然而，迄今为止，缺乏在传染病和临床方面受过双重训练的医生科学家。 药理学谁可以冠军这些药物开发的努力，特别是对NTM。 在这份提案中，候选人将应用临床药理学工具来解决分枝杆菌感染的问题。 治疗，并利用三个资助的临床试验的资源和框架，由 导师和咨询委员会成员。由一个强大的多学科咨询团队提供支持， 在临床药理学、分枝杆菌药物开发、药物计量学和分枝杆菌学方面， 候选人将1）定义阿奇霉素对分枝杆菌的药代动力学-药效学（PK-PD） 通过应用早期杀菌活性（EBA）试验设计（目的1）治疗禽复合体（MAC）肺病; 2） 用PK-毒代动力学（PK-TD）模型确定新型硝基咪唑类抗生素毒性预测因子 (Aim 2）;和3）确定一线结核病治疗与 普伐他汀作为宿主导向治疗（目的3）。每一个目标都将提供一个机会，不仅 学习并实施结核病和非结核病调查的药理学分析方法。的 候选人将获得包括群体PK建模，早期杀菌活性试验设计执行， PK-毒理动力学建模和临床毒性预测工具的开发。 这个K23指导的以患者为导向的研究职业发展奖不仅将促进 研究分枝杆菌治疗，但也支持候选人获得必要的技能，执行 基础和先进的临床药理学分析，领导临床试验，并形成强大的多 机构合作。完成K23后，候选人将成为 具有传染病专业知识的独立临床研究者，应用抗分枝杆菌药理学， 和NTM疗法。