Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

尿液比色法用于儿童和成人结核病药代动力学评价

• 批准号: 10320620
• 负责人: Scott K Heysell
• 金额: $ 20.26万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320620
• 关键词: AIDS clinical trial group; Adherence; Adult; Advisory Committees; Antibiotics; Antitubercular Agents; Area; Award; Biological Assay; Biological Availability; Biomedical Research; Blood; Car Phone; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Chromatography; Clinical; Clinical Research; Clinical Trials; Cold Chains; Collection; Color; Colorimetry; Communicable Diseases; Complement; Development; Development Plans; Diabetes Mellitus; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Drug toxicity; Environment; Ethambutol; Evaluation; Faculty; Fatty acid glycerol esters; Fluoroquinolones; Funding; Glycosuria; Goals; Gold; HIV; Half-Life; Hour; Individual; Ingestion; Integration Host Factors; International; Intervention Studies; K-Series Research Career Programs; Kinetics; Laboratories; Lead; Levaquin; Malnutrition; Mass Spectrum Analysis; Measures; Mentors; Mentorship; Metabolism; Morbidity - disease rate; Moxifloxacin; Oral; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Physicians; Plasma; Population Heterogeneity; Process; Proteinuria; Pyrazinamide; Reader; Regimen; Research; Research Personnel; Resources; Rifampin; Rifamycins; Sampling; Science; Scientist; Seasons; Serum; Specific Gravity; Spectrophotometry; Talents; Testing; Therapeutic; Time; Toxic effect; Training; Treatment Failure; Tuberculosis; Underrepresented Minority; United States; Urine; Variant; Weight; Woman; absorption; acquired drug resistance; appropriate dose; assay development; base; career; career development; drug metabolism; ethnic minority population; experience; field study; healthy volunteer; improved; improved outcome; innovation; isoniazid; meetings; microbial; mortality; novel; novel therapeutics; parent grant; peer; point of care; poor communities; preclinical study; programs; racial minority; recruit; research and development; rifapentine; therapy duration; treatment duration; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY Approach: We propose to test the hypotheses that rifapentine and moxifloxacin urine kinetics will predict relevant serum pharmacokinetic parameters of peak serum concentration (Cmax) and the area under the concentration time curve (AUC0-24hours), and that those urine concentrations can be further quantified by spectrophotometric (colorimetric) assays. Innovation: A urine colorimetric assay for rifapentine and moxifloxacin, two critical drugs in the novel regimen to shorten tuberculosis (TB) treatment duration, could provide a same-day clinical result of pharmacokinetic exposure in settings without access to chromatography or mass spectrometry. Both rifapentine (which requires ingestion of a high fat meal) and moxifloxacin pharmacokinetics may be more significantly altered when the novel regimen is scaled beyond the clinical trial. Consequently, urine colorimetry may prove superior to limited blood draws currently practiced to estimate Cmax or AUC0-24 given the kinetics of drug accumulation in the urine. Impact: Successful completion of these studies will determine the applicability of urine drug kinetics for personalized dosing strategies in rifapentine and moxifloxacin containing anti-TB drug regimens to correct a significant component of TB treatment failure. Significance: Despite curative antibiotics, TB treatment failure is common, leading to morbidity, mortality and acquired drug resistance. Individual pharmacokinetic variability is a primary driver of TB treatment failure leading to drug exposures that are suboptimal for microbial kill. Personalized dose adjustment based on an individual’s serum pharmacokinetics is out-of-reach for the majority of people suffering from TB globally. Environment: Dr. Mohamed’s research complements the aims of the funded parent grant which is currently optimizing later stage urine colorimetric assays for field use in the conventional anti-TB regimen of isoniazid, rifampin, pyrazinamide and ethambutol. Dr. Mohamed joins an international team of researchers with expertise in TB science including pharmacology, assay development and interventional research (led by PI and primary mentor, Dr. Heysell). Dr. Mohamed’s career development will also be supported by seasoned mentor and Division Chief of Infectious Diseases (Dr. Houpt), and importantly, a near-peer junior faculty who has transitioned from a Diversity Supplement support to independent funding (Dr. Moonah). Diversity Supplement Award: The career development plan in this proposal will augment the direct scientific mentorship through the combination of active guidance from internal and external advisory teams (participation in Building Up a Diverse Pipeline of the Biomedical Research Workforce program), technical training/courses and presentation at national/international meetings with the planned goal of submission of two career development awards on the pathway to becoming an independent physician-scientist.

项目摘要 方法：我们建议测试利福丁和莫西沙星尿液动力学的假设 峰血清浓度（CMAX）和面积的相关血清药代动力学参数 浓度时间曲线（AUC0-24小时），可以通过 分光光度法（比色）测定法。 创新：利福丁和莫西法沙星的尿液比色测定法，这是新型方案中的两种关键药物 缩短结核病（TB）治疗持续时间，可以提供药代动力学的同一天临床结果 在不访问色谱或质谱的情况下，在设置中暴露。两者都是利福丁（这需要 摄入高脂餐）和莫西法沙星药代动力学时可能会更明显地改变 新型方案超出了临床试验。因此，尿素法可能比有限 鉴于尿液中药物积累的动力学，目前正在实践的血液来估计CMAX或AUC0-24。 影响：这些研究的成功完成将决定尿液动力学的适用性 利福丁和含有抗TB药物方案的个性化剂量策略，以纠正A 结核病治疗失败的重要组成部分。 意义：尽管治愈抗生素，但结核病治疗衰竭还是很常见的，导致发病率，死亡率和 获得的耐药性。单个药代动力学变异性是结核病治疗失败的主要驱动力 导致药物暴露是微生物杀死的次优。基于一个个性化剂量调整 个人的血清药代动力学对于大多数全球结核病患者来说都是不受欢迎的。 环境：穆罕默德博士的研究完成了资助的父母赠款的目标 优化以下尿液比色测定法在常规抗TB方案中用于现场使用， 利福平，吡嗪酰胺和乙酰胺醇。穆罕默德博士加入了一支具有专业知识的国际研究人员团队 在包括药物在内的结核病科学，测定开发和介入研究（由PI和主要的领导 导师，海塞尔博士）。穆罕默德博士的职业发展也将得到经验丰富的导师和 传染病司令部（Houpt博士），重要的是，有一个近亲的初级教师 从多样性补充支持转变为独立资金（Moonah博士）。 多样性补充奖：该提案中的职业发展计划将增强直接科学 通过内部和外部咨询团队的积极指导结合的遗产（参与） 在建立生物医学研究工作人员计划的多样化的过程中，技术培训/课程 并在国际/国际会议上演讲，计划提交两个职业的目标 发展成为独立身体科学家的途径的发展奖。