Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

项目总结 方法：我们建议检验利福喷丁和莫西沙星的尿动力学将预测的假设。 相关血药动学参数的峰值血药浓度(Cmax)和峰下面积 尿药浓度时间曲线(AUC0-24小时)，这些尿药浓度可通过以下方法进一步量化 分光光度(比色法)分析。 创新：尿液比色法测定利福喷丁和莫西沙星，这是新方案中的两种关键药物 缩短结核病(TB)疗程，可提供当日临床药代动力学结果 暴露在没有层析或质谱学的环境中。利福喷丁(需要 摄入高脂肪食物)和莫西沙星的药代动力学可能会在以下情况下发生更显著的改变 新方案的规模超出了临床试验的范围。因此，尿液比色法可能会被证明优于有限的。 根据药物在尿液中的积聚动力学，目前常用的抽血方法是估算Cmax或AUC0-24。 影响：这些研究的成功完成将确定尿药动学在 利福喷丁和莫西沙星抗结核药物方案的个性化给药策略 结核病治疗失败的重要组成部分。 意义：尽管有治愈的抗生素，但结核病治疗失败是常见的，导致发病率、死亡率和 获得性抗药性。个体药代动力学变异是结核病治疗失败的主要驱动因素 导致接触到的药物对微生物的杀伤力不佳。基于遗传算法的个性化剂量调整 对于全球大多数结核病患者来说，个人的血清药代动力学是遥不可及的。 环境：穆罕默德博士的研究补充了资助父母基金的目标，目前 优化异烟肼常规抗结核方案现场使用的后期尿液比色分析方法， 利福平、吡津酰胺和乙胺丁醇。穆罕默德博士加入了一个拥有专业知识的国际研究团队 在结核病科学方面，包括药理学、化验开发和干预研究(由PI和PRIMARY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 传染病科科长(胡普特博士)，更重要的是，一位近乎同级的初级教员 从多样性补充支助过渡到独立供资(Moonah博士)。 多元化增补奖：这项建议中的职业发展计划将增加直接的科学性 通过内部和外部咨询团队的积极指导相结合进行指导(参与 在建立生物医学研究劳动力计划的多样化管道中)、技术培训/课程 以及在国家/国际会议上介绍，计划的目标是提交两个职业 在成为一名独立的内科医生-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.