Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

项目概要 我们的长期目标是开发一种即时尿检作为治疗药物的快速、非侵入性替代品 抗结核药物监测。该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鉴别低抗结核病结核病患者 药物暴露。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水平低的患者 水平，并具有与结核病管理中其他广泛使用的测试类似的诊断特征。 这一假设的前提是基于我们的工作表明尿液比色法可以准确识别成人 抗结核血浆药物暴露量低的结核病患者。该项目包括两个具体目标。 在目标 1 中，我们将对异烟肼、利福平、 和吡嗪酰胺治疗活动性结核病的成人。我们将对血液和尿液进行采样，以便 定义尿液比色法的接受者操作特征曲线以检测低抗结核药物 暴露，按照血浆药物暴露金标准测量定义（24 小时暴露面积） 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）。 由于治疗药物监测对共病结核病/糖尿病患者的价值已得到证实， 我们将根据糖尿病状况对入学进行分层。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测定的操作特性分析。在目标 2 中，我们将 确定尿液比色法检测低血浆抗结核药物的诊断特征 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（药代动力学分析，然后是接受者操作- 尿液比色法的特征曲线）。拟议研究的基本原理是，一旦接收者 在两个关键的高危人群中建立了尿液比色法的操作特性曲线 结核病患者（患有糖尿病的成人和儿童），将这些测定转化为 可以进行即时检测。然后可以验证尿液比色测定作为一种非侵入性方法 用于优化资源有限环境中的抗结核药物暴露。

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.