Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

项目概要 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 浓度时间曲线（AUC0-24小时），并且这些尿液浓度可以通过以下方式进一步量化 分光光度（比色）测定。 创新：利福喷丁和莫西沙星（新疗法中的两种关键药物）的尿液比色测定 缩短结核病 (TB) 治疗时间，可提供当天的药代动力学临床结果 exposure in settings without access to chromatography or mass spectrometry.两种利福喷丁（需要 摄入高脂肪膳食）和莫西沙星的药代动力学可能会发生更显着的改变 新的治疗方案超出了临床试验范围。因此，尿液比色法可能优于有限的 鉴于尿液中药物蓄积的动力学，目前采用抽血来估计 Cmax 或 AUC0-24。 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 含利福喷丁和莫西沙星的抗结核药物治疗方案的个性化剂量策略，以纠正 结核病治疗失败的重要组成部分。 意义：尽管有治疗性抗生素，但结核病治疗失败很常见，导致发病率、死亡率和 获得性耐药性。 Individual pharmacokinetic variability is a primary driver of TB treatment failure 导致药物暴露不能达到杀灭微生物的最佳效果。根据个人化剂量调整 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目前正在资助的家长补助金的目标 优化后期尿液比色测定，以供异烟肼常规抗结核方案现场使用， 利福平、吡嗪酰胺和乙胺丁醇。穆罕默德博士加入了具有专业知识的国际研究团队 结核病科学领域，包括药理学、检测开发和介入研究（由 PI 和初级研究人员领导） 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 传染病科主任（Dr. Houpt），重要的是，他是一位接近同行的初级教师， transitioned from a Diversity Supplement support to independent funding (Dr. Moonah). 多样性补充奖：本提案中的职业发展计划将增强直接科学 mentorship through the combination of active guidance from internal and external advisory teams (participation 建立生物医学研究人员队伍的多元化管道计划），技术培训/课程 并在国家/国际会议上进行演讲，计划目标是提交两份职业报告 development awards on the pathway to becoming an independent physician-scientist.

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.