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（TB）治疗已经有60多年的历史，但结核病仍然是世界范围内导致死亡的主要原因。旨在提高药物依从性的积极公共卫生努力确实改善了患者的预后，但不能保证治愈。这是因为改善依从性并不能解决降低循环药物浓度和阻碍药物疗效的其他关键因素，如：不合格的仿制药/假药、并发感染、合并症、正常生长发育、遗传变异和临时药物复合。尽管治疗结核病患者的卫生保健提供者意图良好，但如果没有测量药物浓度的手段，根本无法确保达到并维持适当的药物水平。然而，传统的样本采集（采血师进行静脉穿刺，并对样本进行温度控制的处理、储存和运输）在偏远、资源有限的社区是不实用的，这些社区为那些因其环境性质而面临最大治疗失败风险的个人提供服务。这项研究是基于一种普遍假设，即干血斑（DBS）技术可用于促进结核病儿童的药代动力学分析，并提供有关剂量-暴露关系的信息，以指导各种儿科亚群的剂量。本研究活动将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)检查传统静脉穿刺与DBS同时采集的标本中获得的抗结核药物浓度之间的关系，以及3)评估从DBS分离的核酸在影响抗结核暴露/反应的基因分析中的表现。作为一种治疗工具，脑起搏器抽样为生活在偏远、不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性化治疗方法。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，否则这些关系将永远不会在药代动力学研究中得到体现。

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.