Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

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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.