Despite the fact that effective tuberculosis (TB) treatments have been available for over 60 years, TB remains a leading cause of death worldwide. Aggressive public health efforts designed to improve medication adherence do improve patient outcomes but do not guarantee a cure. This is because improving adherence does not address other critical factors that reduce circulating drug concentrations and impede drug efficacy such as: substandard generic/counterfeit drugs, concurrent infections, co-morbid diseases, normal growth and development, genetic variations, and extemporaneous drug compounding. Despite the best intentions of the health care providers that treat patients with TB, there simply is no way to ensure that adequate drug levels are achieved and sustained without a means to measure drug concentrations. However, traditional sample collection (phlebotomist performed venipuncture with temperature controlled sample processing, storage and transport) is not practical in remote, resource-constrained communities serving individuals who, by the very nature of their circumstances, are at the greatest risk of therapeutic failure. This investigation is driven by the general hypothesis that dried blood spot (DBS) technology can be used to facilitate pharmacokinetic analyses in children with tuberculosis and provide information on dose-exposure relationships necessary to guide dosing in various pediatric subpopulations. The activities of this investigation will 1) develop and validate methods for quantitative DBS analysis of first and second line antitubercular drugs, 2) examine the association between antitubercular drug concentrations derived from concurrent specimens collected by traditional venipuncture vs. DBS, and 3) evaluate the performance of nucleic acid isolated from DBS in genetic analyses for mutations that influence antitubercular exposure/response. As a therapeutic tool, DBS sampling offers a safe, effective and inexpensive way to dynamically monitor and individualize treatment for children living in remote, undeveloped communities. As a research tool, DBS technology will allow investigators to validate dose-exposure relationships in populations that would otherwise never be represented in pharmacokinetic studies.
The most appropriate doses of tuberculosis medicines for children in remote, resource-constrained communities remain unclear because these children are never represented in pediatric pharmacokinetic studies that are designed to characterize the dose-exposure relationship. A major contributing factor is the inability to obtain and process traditional blood samples (phlebotomist performed venipuncture with temperature controlled sample processing, storage and transport) in these remote regions. This investigation will develop tools, based on dried blood spot technology, that will overcome the limitations of traditional drug sampling and enable large-scale surveillance (for research and clinical purposes) in rural communities.