Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

项目摘要 方法：我们建议检验利福喷丁和利福沙星尿动力学预测 相关血清药代动力学参数的血清峰浓度（Cmax）和峰下面积 浓度时间曲线（AUC 0 - 24小时），并且这些尿液浓度可以通过以下方法进一步定量： 分光光度（比色）测定。 创新：新方案中两种关键药物利福喷丁和利福沙星的尿液比色测定 缩短结核病（TB）治疗时间，可提供当天的临床药代动力学结果 在没有色谱或质谱仪的环境中暴露。利福喷丁（需要 摄入高脂肪食物），当摄入高脂肪食物时， 新方案的规模超出了临床试验。因此，尿比色法可证明上级有限的 鉴于药物在尿液中蓄积的动力学，目前用于估计Cmax或AUC 0 -24的抽血。 影响：这些研究的成功完成将确定尿液药物动力学的适用性， 在含利福喷丁和利福沙星的抗结核药物方案中， 结核病治疗失败的重要组成部分。 意义：尽管有治愈性抗生素，结核病治疗失败是常见的，导致发病率，死亡率和死亡率。 获得性耐药性个体药代动力学变异性是结核病治疗失败的主要驱动因素 导致药物暴露对于微生物杀灭而言是次优的。根据患者的具体情况进行个性化剂量调整 个体的血清药代动力学对于全球大多数患有TB的人来说是遥不可及的。 环境：穆罕默德博士的研究补充了资助父母赠款的目标，目前 优化用于常规异烟肼抗TB方案的现场使用的后期尿比色测定， 利福平、吡嗪酰胺和乙胺丁醇。穆罕默德博士加入了一个国际研究团队， 结核病科学，包括药理学、检测开发和干预研究（由PI和主要 导师，Heysell博士）。穆罕默德博士的职业发展也将得到经验丰富的导师的支持， 传染病科科长（博士Houpt），重要的是，一个接近同行的初级教师谁拥有 从多元化补充支持过渡到独立资助（Moonah博士）。 多样性补充奖：本提案中的职业发展计划将增加直接的科学 通过内部和外部咨询小组的积极指导相结合的指导（参与 建立生物医学研究劳动力多元化管道计划）、技术培训/课程 并在国家/国际会议上发言，计划提交两份职业报告， 在成为一名独立的医生科学家的道路上获得发展奖。

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.