Document text
Principal Investigator: Scott K Heysell
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $785,512
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <0-11 years old><21+ years old><Adult><Adult Human><Adverse Experience><Adverse event><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibiotics against tuberculosis><Antitubercular Agents><Antitubercular Antibiotics><Antitubercular Drugs><Area><Assay><Attenuated><Bacterial Drug Resistance><Benemycin><Bioassay><Biological Assay><Biological Markers><Blood Serum><Bypass><Cessation of life><Characteristics><Child><Child Youth><Children (0-21)><Clinical><Cold Chains><Collection><Colorimetry><Death><Diarrhea><Disease><Disorder><Dose><Drug Kinetics><Drug Targeting><Drugs><Dysfunction><Enteral><Enteric><Evaluation><Excretory function><Exposure to><Failure><Feces><Functional disorder><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><Individual><Inflammation><Intervention><Intervention Strategies><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal Mass><Intestinal permeability><Kinetics><Knowledge><Lung TB><Lung Tuberculosis><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Malabsorption Syndromes><Malnutrition><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Medication><Medicine><Miscellaneous Antibiotic><Morbidity><Morbidity - disease rate><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Nutritional Deficiency><Outcome><Participant><Pathogen detection><Permeability><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phase><Physiopathology><Point-of-Care Systems><Population><Predisposition><Process><Pulmonary TB><Pulmonary Tuberculosis><Randomized><Regimen><Resistance><Rifadin><Rifampicin><Rifampin><Rifamycins><Rimactane><Role><Safety><Selection for Treatments><Serum><Spectrophotometry><Staining method><Stains><Susceptibility><System><TB antibiotics><TB drugs><TB infection><TB therapy><TB treatment><Tablets><Tanzania><Testing><Time><Treatment Failure><Treatment outcome><Tuberculosis><Tuberculosis antibiotics><Tuberculostatic Agents><Undernutrition><Urine><Weight><adulthood><age stratification><anti-TB><anti-TB drugs><anti-bacterial drug resistance><anti-bacterial drug resistant><anti-bacterial resistance><anti-bacterial resistant><anti-tuberculosis><anti-tuberculosis drugs><antiTB><antibiotic against TB><attenuate><attenuates><bactericidal><bactericide><bio-markers><biologic marker><biomarker><bowel inflammation><clinical predictors><clinical relevance><clinical significance><clinically relevant><clinically significant><cohort><conventional dosage><conventional dosing><curative intervention><curative therapeutic><curative therapy><curative treatments><dietary deficiency><disseminated TB><disseminated tuberculosis><drug-sensitive><drug/agent><efficacy study><efficacy testing><enteral pathogen><enteric pathogen><enteropathogen><excretion><gastrointestinal><gastrointestinal absorption disorder><gut inflammation><improved><individualized strategies><infection due to Mycobacterium tuberculosis><inflamed bowel><inflamed gut><inflamed intestine><interventional strategy><intestinal inflammation><intestinal malabsorption><intestinal pathogen><intestine pathogen><kids><lab equipment><laboratory equipment><laboratory technology><malabsorption><malnourished><mortality><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><pathogen><pathophysiology><personalized strategies><point of care><preservation><randomisation><randomization><randomized control study><randomized, controlled study><randomly assigned><resistance to anti-bacterial><resistant><resistant to anti-bacterial><response><response to therapy><response to treatment><selection of treatment><social role><spectrophotometer><stool><temporal measurement><temporal resolution><therapeutic response><therapy failure><therapy response><therapy selection><time measurement><traditional dosage><traditional dosing><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><treatment response><treatment responsiveness><treatment selection><trial design><tuberculosis drugs><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><urinary><weights><youngster>