Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

项目总结 我们的长期目标是开发一种快速、非侵入性的治疗药物替代疗法--点尿法。 监测抗结核药物。这个应用程序的总体目标是生成接收器操作- 尿液比色法特征曲线在低抗结核患者鉴别中的应用 接触毒品。研究人群将包括患有活动性结核病的儿童和成人。我们的中央 假设尿液比色法将成功识别抗结核血浆药物含量较低的患者 水平，这样做的诊断特征类似于结核病管理中广泛使用的其他检测方法。 这一假设的前提是基于我们的工作，即尿液比色法准确识别成人 低抗结核血浆药物暴露的肺结核患者。该项目包括两个具体目标。 在目标1中，我们将进行一项前瞻性、观察性、密集的异烟肼、利福平、 在接受活动性结核病治疗的成年人中使用吡津胺。我们会同时采集血液和尿液样本，以便 确定尿液比色法检测低浓度抗结核药物的受试者-工作特性曲线 暴露，由血浆药物暴露的黄金标准衡量(24小时以下的区域 浓度-时间曲线，根据每个参与者的群体药代动力学模型估计)。 由于治疗药物监测在合并结核病/糖尿病患者中的已被证明的价值， 我们将根据糖尿病状况对注册人数进行分层。这种分层将支持调整后的接收器- 以糖尿病为协变量的尿液比色分析的操作特性分析。在目标2中，我们将 尿液比色法检测低血清抗结核药物的诊断特点 高负担环境中患有活动性结核病的儿童和青少年的暴露情况(坦桑尼亚)， 遵循类似的统计分析计划(先进行药代动力学分析，然后进行接受者操作- 尿液比色法特征曲线)。拟议研究的基本原理是，一旦接收者- 在两个高危人群之间建立了尿液比色法的操作特征曲线 结核病患者(患有糖尿病的成人和儿童)，将这些检测翻译成 可以执行护理点测试。然后，尿液比色分析可以被确认为一种非侵入性方法。 用于在资源有限的情况下优化抗结核药物的暴露。

PROJECT SUMMARY Our long-term goal is to develop a point-of-care urine test as a rapid, non-invasive surrogate for therapeutic drug monitoring of anti-tuberculosis drugs. The overall objective of this application is to generate receiver-operating- characteristic curves for urine colorimetry in the identification of tuberculosis patients with low anti-tuberculosis drug exposures. The study population will include children and adults with active tuberculosis. Our central hypothesis is that urine colorimetry will successfully identify patients with low anti-tuberculosis plasma drug levels, and do so with diagnostic characteristics similar to other widely used tests in tuberculosis management. The premise for this hypothesis is based on our work showing that urine colorimetry accurately identified adult tuberculosis patients with low anti- tuberculosis plasma drug exposures. This project includes two specific aims. In Aim 1, we will conduct a prospective, observational, intensive pharmacokinetic study of isoniazid, rifampin, and pyrazinamide among adults treated for active tuberculosis. We will sample both blood and urine in order to define the receiver-operating-characteristic curve for urine colorimetry to detect low anti-tuberculosis drug exposures, as defined by the gold standard measure of plasma drug exposure (the area under the 24-hour concentration-versus-time curve, estimated from the population pharmacokinetic model for each participant). Because of the demonstrated value of therapeutic drug monitoring in co-morbid tuberculosis/diabetes patients, we will stratify enrollment based on diabetes mellitus status. This stratification will support adjusted receiver- operating-characteristic analyses of the urine colorimetric assay with diabetes as a covariate. In Aim 2, we will determine the diagnostic characteristics of urine colorimetry to detect low plasma anti-tuberculosis drug exposures among children and adolescents with active tuberculosis disease in a high-burden setting (Tanzania), following a similar statistical analysis plan (pharmacokinetic analysis followed by receiver-operating- characteristic curves for urine colorimetry). The rationale for the proposed research is that once receiver- operating-characteristic curves for urine colorimetry are established among two key groups of high-risk tuberculosis patients (adults with co-morbid diabetes mellitus and children), translation of these assays to a point-of-care test can be performed. The urine colorimetric assay can then be validated as a noninvasive method for optimizing anti-tuberculosis drug exposures in resource-limited settings.