Tuesday, February 4, 2025
2/4/2025
PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is a major cause of morbidity and mortality worldwide with most deaths occurring in individuals infected with highly treatable, drug sensitive stains. Individual pharmacokinetic variability is an important driver of TB treatment failure particularly among undernourished populations, and sub-target serum drug concentrations are associated with delayed response to treatment, death, and acquired bacterial drug resistance. We have demonstrated that measuring an individual’s serum pharmacokinetics and personalizing a dose adjustment can improve TB treatment outcomes. In TB endemic settings, medicines are typically only available in fixed-dosed combination tablets as lack of cold chain preservation of serum and specialized laboratory equipment hinder the timely measurement of drug concentrations. With the current 5R01 AI137080 we developed a process to quantify TB drug concentrations from urine analyzed with a benchtop spectrophotometer bypassing the cold chain (Point-of-care Evaluation of Exposure to TB drugs- PEE-TB). Focusing on rifampin for drug-susceptible TB, we found urinary rifampin excretion as measured by spectrophotometry at feasible collection intervals predicted clinically significant targets of serum exposure of a full dosing interval in children and adults with active TB. We also discovered that stool enteropathogen burden at TB treatment initiation was associated with reduced rifampin serum exposures among children with undernourishment and stool biomarkers suggested a malabsorption mechanism. Therefore, our central hypothesis for this renewal is that in undernutrition related TB, pharmacokinetic variability is driven by the burden of enteric pathogens via malabsorption, yet a clinically significant proportion of sub-target drug concentrations can be corrected by measurement of urinary drug excretion. We propose a randomized and controlled study of the PEE-TB based dose adjustment intervention for rifampin to test the efficacy of the platform in increasing rifampin serum concentrations to target, and the overall safety of the dose personalization strategy in children and adults. In this setting of high TB and undernutrition burden, the trial design will also facilitate study of the mechanisms for pharmacokinetic variability including the presence of total or species-specific enteropathogens, or enteropathy related to intestinal inflammation, functional intestinal mass and intestinal permeability, and whether enteropathogens and/or enteropathy blunt the pharmacokinetic response to PEE-TB based rifampin dose personalization.
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