Reinforcing old warriors to treat Mycobacterium kansasii in shorter duration

强化老战士在更短的时间内治疗堪萨斯分枝杆菌

• 批准号: 10250999
• 负责人: Shashi Kant
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250999
• 关键词: Academia; Address; Affect; American; Apical; Bacteria; Biological Assay; Chest; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Computer Assisted; Confidence Intervals; Consumption; Data; Differential Equation; Disease; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Drug resistance; Equation; Ethambutol; Extinction (Psychology); Fiber; Goals; Growth; Guidelines; Immune; Immunocompetent; Industry; Infection; Knowledge; Laboratory Study; Lung; Lung diseases; Mathematical Model Simulation; Mathematics; Measures; Modeling; Mycobacterium Infections; Mycobacterium kansasii; Mycobacterium tuberculosis; NIH Program Announcements; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pleural; Population; Pre-Clinical Model; Preclinical Drug Development; Predisposition; Prevalence; Probability; Randomized; Recommendation; Regimen; Relapse; Research; Rifampin; Safety; Sampling; Societies; Sputum; Surface; Taiwan; Time; Toxic effect; Translating; Translations; Treatment Protocols; Treatment outcome; Tube; Tuberculosis; Variant; acquired drug resistance; appropriate dose; base; chemotherapy; control trial; design; drug development; drug standard; experimental study; in silico; isoniazid; lead optimization; mathematical model; mortality; mycobacterial; non-linear transformation; non-tuberculosis mycobacteria; optimal treatments; pre-clinical; prospective; response; simulation; standard care; synergism; therapy development; therapy duration; tool development; treatment duration; treatment optimization; tuberculosis drugs

PROJECT SUMMARY Mycobacterium kansasii (M. kansasii) is the second most common non-tuberculous mycobacteria (NTM) causing disease in both immune-competent and immune-compromised patients. In contrast to other NTMs, M. kansasii pulmonary disease resembles that of tuberculosis and may therefore be a target for tuberculosis-like short-course chemotherapy. Currently the course of chemotherapy recommended by the American Thoracic Society is a combination regimen of isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15-25 mg/kg/day) given daily for at least 12 months beyond when the bacteria is no longer cultured from the sputum. This prolonged duration is far longer than the 6-month tuberculosis regimen. The drug doses currently recommended are not optimized for M. kansasii nor rigorously studied in combination with other drugs of potential synergy, antagonism or additivity in the pre-clinical models, rather obtained from tuberculosis drug trials. As a result, the treatment outcomes are relatively poor despite such a long therapy duration. The studies proposed here will – (1) determine the optimal dose of isoniazid, rifampin, and ethambutol for treatment of M. kansasii, (2) add the drugs at exposure showing synergy/additivity between drug pair to develop optimal dose combination regimen, (3) perform mathematical modeling and clinical trial simulations to determine the therapy duration with new regimen. Since the proposed drugs are already in use for treatment of M. kansasii with known safety and toxicity data, we expect our new regimens can readily be advanced into the clinics. Our approach is less time-consuming compare to the traditional drug development strategies that can take years from lead optimization to combination therapy development.

项目摘要 Kansasii分枝杆菌（M. kansasii）是第二大常见的无菌分枝杆菌（NTM） 引起免疫能力和免疫疾病患者的疾病。与其他NTM相比。 Kansasii肺疾病类似于结核病，因此可能是结核病样的靶标 短道化疗。目前，美国胸部推荐的化学疗法进程 社会是Isoniazid（300 mg/day），Rifampin（600 mg/day）和Ethambutol（15-25）的组合方案 Mg/kg/day）每天至少在不再从痰液中培养细菌的情况下至少12个月。 该延长持续时间远远超过6个月的结核病治疗方案。目前的药物剂量 建议不针对Kansasii进行优化，也不是严格研究的其他药物 潜在的协同作用，拮抗或添加性在临床前模型中，而不是结核病药物 试验。结果，治疗结果是相对较差的目的地，因此长期治疗持续时间。研究 这里提出的将 - （1）确定异念珠菌，利福平和ethambutol的最佳剂量用于治疗。 Kansasii，（2）在暴露时添加药物，显示药物对之间的协同/添加性以发展最佳剂量 组合方案（3）执行数学建模和临床试验模拟以确定治疗 新方案的持续时间。由于所提出的药物已经用于治疗kansasii。 安全性和毒性数据，我们希望我们的新方案很容易进入诊所。我们的方法是 与传统的药物开发策略相比，较耗时的时间可能需要数年 对组合疗法开发的优化。