Urine Colorimetry for Tuberculosis Pharmacokinetics Evaluation in Children and Adults

尿液比色法用于儿童和成人结核病药代动力学评价

• 批准号: 10488657
• 负责人: Scott K Heysell
• 金额: $ 66.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488657
• 关键词: Adolescent; Adult; Antitubercular Agents; Area; Biological Assay; Blood; Blood specimen; Caring; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Colorimetry; Communicable Diseases; Data; Diabetes Mellitus; Diagnostic; Disease; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Drug resistance; Enrollment; Environment; Evaluation; Goals; Gold; Guidelines; Hour; Infection; Inferior; Laboratories; Measures; Metabolism; Methods; Non-Insulin-Dependent Diabetes Mellitus; Organizational Objectives; Outcome; Participant; Patient-Focused Outcomes; Patients; Performance; Pharmaceutical Preparations; Plasma; Population; Pyrazinamide; ROC Curve; Regimen; Relapse; Research; Resource-limited setting; Resources; Rifampin; Sampling; Statistical Data Interpretation; Stratification; Tanzania; Techniques; Technology; Testing; Therapeutic; Time; Treatment Failure; Treatment outcome; Tuberculosis; Urine; Validation; Work; World Health Organization; absorption; base; comorbidity; diagnostic accuracy; experience; high risk population; improved; insight; isoniazid; novel strategies; pharmacokinetic model; point of care; point of care testing; prospective; standard measure; study population; time interval; translation assay; tuberculosis drugs; tuberculosis treatment

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.

项目摘要 我们的长期目标是为治疗药物的快速，无创替代物开发一种护理点测试 监测抗结核药物。该应用程序的总体目的是生成接收器操作 - 尿液比色的特征曲线在鉴定抗结核低的结核病患者中 药物暴露。研究人群将包括患有活跃结核病的儿童和成年人。我们的中心 假设是，尿液比色将成功鉴定出低抗结核血浆药物的患者 水平，并以类似于结核病管理中其他广泛使用的测试的诊断特征来做到这一点。 该假设的前提是基于我们的工作，表明尿液比色准确鉴定出成年人 抗结核血浆药物暴露低的结核病患者。该项目包括两个具体目标。 在AIM 1中，我们将对异烟肼，利福平，一项前瞻性，观察性，密集的药代动力学研究， 和接受活性结核病治疗的成年人中的吡嗪酰胺。我们将采样血液和尿液，以便 定义尿液比色的接收器 - 操作特征曲线，以检测低抗结核药物 曝光，如血浆药物暴露的黄金标准度量所定义的（24小时下的面积 从每个参与者的人群药代动力学模型估计的浓度与时间曲线）。 由于在合并性结核病/糖尿病患者中的治疗药物监测的价值，因此 我们将根据糖尿病状态对注册进行分层。该分层将支持调整后的接收器 - 用糖尿病作为协变量对尿液比色测定法的工作特征分析。在AIM 2中，我们将 确定尿液比色法的诊断特征，以检测低血浆抗结核药物 在高负荷环境（坦桑尼亚）中患有活性结核病的儿童和青少年的暴露， 遵循类似的统计分析计划（药代动力学分析，然后进行接收器操作 尿度量法的特征曲线）。拟议研究的理由是，一旦接收器 在高风险的两个关键组中，建立了用于尿度量法的操作特征曲线 结核病患者（患有糖尿病的成年人和儿童），这些测定法转换为 可以执行护理点测试。然后可以将尿素比色测定法作为无创方法进行验证 用于优化在资源有限的环境中进行抗结核药物暴露。