Investigating Multiple PK and PD Relationships for TB-HIV (IMPPRove TB-HIV)

调查 TB-HIV 的多重 PK 和 PD 关系 (IMPPRove TB-HIV)

• 批准号: 10882249
• 负责人: Kelly E. Dooley
• 金额: $ 81.73万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882249
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Affect; Antitubercular Agents; Bacteria; Biological; Biological Response Modifier Therapy; Blood; COVID-19; Cessation of life; Clinical; Cohort Studies; Collaborations; Collection; Complement; DNA; Databases; Disease; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Dryness; Enrollment; Epidemiology; Exposure to; Failure; Funding; Genes; Genetic Polymorphism; Genotype; Geography; Goals; HIV; HIV/TB; Hair; Health; Individual; Inflammation; Intermediate resistance; International; Knowledge; Lung; Lung diseases; Measures; Mediating; Minority Groups; Modeling; Mutation; Mycobacterium tuberculosis; Outcome; Participant; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Play; Prevention; Pulmonary Tuberculosis; Pyrazinamide; Recurrence; Relapse; Research; Research Design; Research Personnel; Resistance; Rifampin; Risk; Role; Sampling; Science Enrichment; Sentinel; Site; Spottings; Sputum; Toxic effect; Treatment Failure; Treatment outcome; Tuberculosis; United States National Institutes of Health; Viremia; Work; acquired drug resistance; care outcomes; co-infection; cohort; design; experience; follow-up; genome sequencing; high risk; improved; isoniazid; lung health; lung injury; mortality; patient population; pharmacokinetics and pharmacodynamics; pharmacometrics; pill; prospective; resistance mutation; respiratory; respiratory health; sociodemographic factors; sociodemographics; therapeutic target; treatment response; tuberculosis drugs; tuberculosis treatment; whole genome

PROJECT SUMMARY Tuberculosis (TB) is the leading infectious cause of mortality globally after COVID-19. TB and HIV interact synergistically, each worsening the outcomes of the other. A key driver of unfavorable TB treatment outcomes is suboptimal drug exposures. However, target drug concentrations of first-line TB drugs and cumulative exposure thresholds needed for optimal clinical outcomes, post-TB lung health, and prevention of emergence of resistance are not defined, particularly in programmatic settings. In our study entitled “Investigating Multiple PK and PD Relationships for TB-HIV (IMPPRove TB-HIV)," we will leverage the Tuberculosis Sentinel Research Network (TB SRN), a large global platform cohort study for coordinated observational TB research conducted among persons with pulmonary TB with and without HIV, within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium in six IeDEA regions, to conduct pharmacokinetic-pharmacodynamic (PK-PD) analyses, using a nested case-cohort design. We will measure individual PK via collection of dried blood spots (DBS), which are easy to collect, store, and ship, and cumulative drug exposure in hair, which reflects both adherence and PK. In Aim 1 (PK-PD aim), we will examine the impact of TB drug PK and cumulative drug exposure on risk of unfavorable TB treatment outcomes (death, failure, recurrence) among individuals with pulmonary TB, with or without HIV. In Aim 2 (PK-resistance aim), we will investigate the impact of drug exposures on emergence of TB drug resistance mutations. In Aim 3 (PK-lung health aim), we will evaluate the association between anti-TB drug exposures and post-TB lung disease and longitudinal lung health. Thus, the IMPPRove study aims to elucidate the relationships between drug exposures and unfavorable TB treatment outcomes, poor lung health, and resistance under field conditions, in a large multinational patient population, taking into account HIV status and other factors known to affect these outcomes. The goal is to inform optimization of TB treatment (right dose, right patient) to improve clinically-important outcomes for patients.

项目摘要 结核病（TB）是共证19之后全球死亡率的主要传染病。结核病和艾滋病毒相互作用 从协同的角度来看，每个人都想知道对方的结果。不利的结核病治疗的关键驱动力 结果是次优的药物暴露。但是，一线TB药物的靶向药物浓度和 最佳临床结果，结核病后健康和预防所需的累积暴露阈值 不确定电阻的出现，尤其是在程序设置中。在我们的研究中 “研究TB-HIV（IMPPROVE TB-HIV）的多个PK和PD关系，”我们将利用 结核前哨研究网络（TB SRN），这是一项大型全球平台队列研究，用于协调 观察性结核病研究在患有和没有HIV的肺结核病患者中进行 评估IADS（IEDEA）财团的国际流行病学数据库，以进行 使用嵌套的病例 - 可容纳设计，对药代动力学 - 剂量动力学（PK-PD）分析进行了分析。我们将衡量 单个PK通过易于收集，存储和运送的干血点（DB）收集的单个PK，并且 头发中的累积药物暴露，这既反映依从性又反映PK。在AIM 1（PK-PD AIM）中，我们将 检查结核病药物PK和累积药物暴露对不利结核治疗风险的影响 患有肺结核的个体的结果（死亡，失败，复发），有或没有HIV。在目标2中 （PK抗性目的），我们将研究药物暴露对结核病耐药性出现的影响 突变。在AIM 3（PK-Lung Health Aim）中，我们将评估抗TB药物暴露之间的关联 结核病后肺部疾病和纵向肺健康。这是Impprove研究旨在阐明 药物暴露与不利的结核病治疗结果，肺部健康不良和 在田间条件下，在大型跨国患者人群中，考虑到艾滋病毒状况 以及已知影响这些结果的其他因素。目的是告知TB治疗的优化（正确 剂量，正确的患者）改善患者的临床重要预后。