Low Cost Monitoring Strategy to Optimize Tuberculosis Treatment in Children

描述(由申请人提供)：尽管有效的结核病治疗已有60多年的历史，但结核病仍然是全球主要的死亡原因。旨在改善服药依从性的积极公共卫生努力确实改善了患者的结果，但不能保证治愈。这是因为，提高依从性并没有解决降低流通药物浓度和阻碍药物疗效的其他关键因素，例如：不合格的仿制药/假药、并发感染、并存疾病、正常生长和发育、基因变异和即兴药物组合。尽管治疗结核病患者的卫生保健提供者的意图是好的，但如果没有测量药物浓度的手段，就无法确保达到和维持足够的药物水平。然而，传统的样本采集(采血员通过温度控制的样本处理、储存和运输进行静脉穿刺术)在偏远、资源有限的社区是不现实的，因为个人的情况本身就是治疗失败的最大风险。这项研究是由以下普遍假设推动的，即干血斑点(DBS)技术可用于促进结核病儿童的药代动力学分析，并提供必要的剂量-暴露关系信息，以指导不同儿科亚群的给药。这项研究的活动将1)开发和验证一线和二线抗结核药物的DBS定量分析方法，2)检查从传统静脉穿刺术同时收集的标本中获得的抗结核药物浓度与DBS之间的关联，以及3)评估从DBS中提取的核酸在影响抗结核暴露/反应的突变的遗传分析中的表现。作为一种治疗工具，DBS抽样为生活在偏远、欠发达社区的儿童提供了一种安全、有效和廉价的动态监测和个体化治疗的方法。作为一种研究工具，DBS技术将允许研究人员验证人群中的剂量-暴露关系，否则这些关系永远不会出现在药代动力学研究中。 公共卫生相关性：偏远、资源有限的社区的儿童最合适的结核病药物剂量仍不清楚，因为这些儿童从未出现在旨在描述剂量-暴露关系的儿科药代动力学研究中。一个主要原因是在这些偏远地区无法获得和处理传统的血液样本(抽血者通过温度控制的样本处理、储存和运输进行静脉穿刺术)。这项调查将开发基于干血斑技术的工具，克服传统药物采样的限制，并在农村社区实现大规模监测(用于研究和临床目的)。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.