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: 10371264
• 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/10371264
• 关键词: Adverse event; Advisory Committees; Antibiotic Resistance; Antibiotics; Antimycobacterial Agents; Area; Azithromycin; Back; 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; Enrollment; Enzymes; Evaluation; Funding; Future; Goals; Hepatotoxicity; Immune response; Incidence; Investigation; Kinetics; Knowledge; Lead; Learning; Lung; Lung diseases; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Microbiology; Modeling; Mycobacterium Infections; Mycobacterium avium Complex; New Agents; Nitroimidazoles; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; 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; base; design; drug development; drug-sensitive; high risk; improved; in vivo; lung injury; minimal inhibitory concentration; model development; multidisciplinary; mycobacterial; non-tuberculosis mycobacteria; novel; novel therapeutics; pharmacokinetic model; pharmacometrics; response; screening; skills; standard care; standard of care; success; tool; treatment effect; trial design; 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.

项目摘要/摘要 分枝杆菌感染的全球负担仍然令人震惊，有超过1000万个新结核病（TB） 2019年的病例和120万人死亡，以及最近无结核分枝杆菌（NTM）的发病率上升。 TB和NTM的治疗都受到长期组合抗生素，耐药性， 毒性，药物相互作用和亚最佳功效。在没有许多新代理商的几十年后，有 现在，共同努力识别和整合新型药物，优化现有药物并增强宿主免疫 回复。临床药理学纳入整个药物开发时，定义了关键关系 在药物暴露和作用（或毒性）之间，确定关键相互作用并增强治疗成功。 但是，迄今 可以支持这些药物开发工作的药理学，尤其是针对NTM。 在此提案中，候选人将应用临床药理学工具来分枝杆菌 治疗和利用三项资助的临床试验的资源和框架。 导师和咨询委员会成员。由具有专业知识的强大多学科咨询团队的支持 在临床药理学，分生不清药物开发，药物测量学和分枝杆菌学上 候选人将1）定义分枝杆菌的阿奇霉素的药代动力学 - 症状动力学（PK-PD） 通过应用早期杀菌活性（EBA）试验设计（AIM 1），鸟类复合物（MAC）肺部疾病； 2） 使用PK毒性动力学（PK-TD）建模确定新硝基咪唑抗生素的毒性预测指标 （目标2）; 3）确定一线结核病治疗和 pravastatin作为宿主指导的疗法（AIM 3）。这些目标中的每一个都将为不仅提供机会 学习但还实施了用于研究结核病和NTM的药理分析方法。这 候选人将获得技能，包括人口PK建模，执行早期杀菌活动试验设计， PK刺激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有助于提高 对分枝杆菌治疗学的研究，但也支持候选人获得所需的技能 基本和先进的临床药理学分析，铅临床试验并形成强大的多种 机构合作。该K23完成后，候选人将成为一个很好的位置 独立临床研究者具有传染病专业知识，应用抗菌药理学， 和NTM疗法。