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）治疗已经存在了60多年，但TB仍然是全球主要的死亡原因。旨在提高药物依从性的积极的公共卫生努力确实改善了患者的预后，但并不能保证治愈。这是因为提高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，例如：不合格的仿制药/假药、并发感染、共病、正常生长和发育、遗传变异和临时药物混合。尽管治疗结核病患者的卫生保健提供者的意图是最好的，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（抽血者进行静脉穿刺，并进行温度控制的样本处理、储存和运输）在偏远、资源有限的社区是不切实际的，因为这些社区的个人由于其环境的性质，面临着最大的治疗失败风险。这项研究是由一般假设驱动的，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，并提供指导各种儿科亚群给药所需的剂量-暴露关系信息。本研究的活动将：1）开发和验证一线和二线抗结核药物定量DBS分析的方法，2）检查通过传统静脉穿刺与DBS采集的并行标本中的抗结核药物浓度之间的相关性，3）评价DBS分离的核酸在影响抗结核药物暴露/反应的突变遗传分析中的性能。作为一种治疗工具，DBS采样提供了一种安全，有效和廉价的方式来动态监测和个性化治疗的儿童生活在偏远，不发达的社区。作为一种研究工具，DBS技术将使研究人员能够验证人群中的剂量-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。 公共卫生相关性：对于偏远、资源有限社区的儿童，结核病药物的最合适剂量仍不清楚，因为这些儿童从未参与旨在描述剂量-暴露关系的儿科药代动力学研究。一个主要的促成因素是在这些偏远地区无法获得和处理传统的血液样本（抽血者进行静脉穿刺，并进行温度控制的样本处理、储存和运输）。这项调查将开发基于干血点技术的工具，以克服传统药物取样的局限性，并使农村社区能够进行大规模监测（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.