Drug-drug interactions and kidney disease in hospitalized patients

住院患者的药物相互作用和肾脏疾病

基本信息

批准号：
10531253
负责人：
Todd Anthony Miano
金额：
$ 15.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531253
关键词：
Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Address Admission activity Adverse event Affect Amiodarone Animal Model Antibiotics Antimicrobial Resistance Binding Proteins Chronic Kidney Failure Clinical Cohort Studies Creatinine Data Database Management Systems Databases Disease Drug Exposure Drug Interactions Drug Kinetics Drug Modelings Drug toxicity Enzymes Fostering Funding Future Generations Goals Health Health system Hepatic Hospitalization Hospitals Human Infection Injury Inpatients Investigation Kidney Kidney Diseases Knowledge Lead Life Measures Mediating Metabolism Methodology Methods Molecular Profiling Nature Outcome Outcome Study Patients Pattern Pharmaceutical Preparations Pharmacoepidemiology Pharmacology Pharmacotherapy Physiology Piperacillin-Tazobactam Polypharmacy Population Prevention strategy Property Prospective cohort Prospective, cohort study Proteins Renal function Research Research Design Research Personnel Retrospective cohort study Risk Role Safety Sepsis Severities Source Statistical Models Testing Toxic effect Training United States Department of Veterans Affairs Vancomycin Vulnerable Populations Warfarin Work burden of illness clinical effect clinically significant cohort design disorder risk drug development epidemiology study experience improved insight medication safety models and simulation nephrotoxicity novel novel strategies pharmacokinetic model physiologically based pharmacokinetics post gamma-globulins predictive modeling prevent preventive intervention prospective response rosuvastatin septic patients simulation skills translational approach translational model virtual

项目摘要

PROJECT SUMMARY As polypharmacy becomes increasingly common in patients with kidney disease, drug-drug interactions (DDIs), the phenomenon of one drug altering the effect of another drug, grow as potential sources of preventable harm in this vulnerable population. The clinical impacts of DDIs are poorly understood, particularly in the hospital setting, where up to half of patients have acute or chronic kidney disease. Further, the potential for bidirectional relationships between kidney disease and DDIs—with kidney disease functioning as both an outcome of DDIs and a baseline factor that alters DDI severity—complicates epidemiologic study and necessitates novel methodologic approaches. This proposal aims to improve the safety of pharmacotherapy in patients with kidney disease through the following broad objectives: 1) examine whether commonly used antibiotics in the hospital setting interact to increase the risk of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD); 2) examine whether changes in kidney function in turn produce variability in DDI severity; 3) train the applicant in renal pharmacoepidemiology, prospective research design and analysis, and pharmacokinetic simulation methods, which will enable a novel translational approach to DDI research; and 4) provide the preliminary data and mechanistic insights for future R01 funded studies that quantify the health impacts of DDIs in the kidney disease population and develop preventive interventions. The applicant will integrate the results from large scale pharmacoepidemiologic studies, prospective cohort studies, and simulation models to achieve the stated objectives. The applicant will first determine the impact of a potential DDI between two common antibiotics on inpatient AKI risk and subsequent CKD using a large-scale health system database and prospective cohort study (Aim 1). The applicant will then examine the effect of kidney disease on the magnitude of a DDI mediated by hepatic CYP450 inhibition using two distinct, yet complementary approaches: developing a pharmacokinetic simulation model of the interaction, followed by a retrospective cohort study of the same interaction (Aim 2). Integration of methods will provide insights into the effects of kidney disease on CYP inhibition that wouldn't be possible with either method in isolation. This proposal will train the candidate in renal pharmacoepidemiology, advanced statistical modeling, and pharmacokinetic simulation, and have important implications for drug safety in the 35 million hospital admissions each year. This research will generate new knowledge extending beyond the specific drugs under study and foster the candidate's progression towards becoming an independent investigator in renal pharmacoepidemiology.

项目概要随着多重用药在肾病患者中变得越来越普遍，药物间相互作用（DDI），一种药物改变另一种药物作用的现象，正在成为潜在的来源对于这一弱势群体的可预防伤害，人们对 DDI 的临床影响知之甚少，尤其是。在医院环境中，多达一半的患者患有急性或慢性肾脏疾病。肾脏疾病和 DDI 之间的双向关系——肾脏疾病既是一种 DDI 的结果和改变 DDI 严重程度的基线因素——使流行病学研究变得复杂需要新的方法论。该提案旨在通过以下方式提高肾病患者药物治疗的安全性：以下广泛目标：1) 检查医院环境中常用的抗生素是否与增加急性肾损伤 (AKI) 和随后的慢性肾病 (CKD) 的风险；2) 检查肾功能的变化是否会导致 DDI 严重程度的变化；3) 对申请人进行肾脏方面的培训；药物流行病学、前瞻性研究设计和分析以及药代动力学模拟方法，这将为 DDI 研究提供一种新颖的转化方法；4) 提供初步数据和未来 R01 资助的研究的机制见解，这些研究量化 DDI 对肾脏的健康影响疾病人群并制定预防性干预措施。申请人将整合大规模药物流行病学研究的结果、前瞻性研究申请人将首先确定实现既定目标的队列研究和模拟模型。两种常见抗生素之间潜在的 DDI 对住院患者 AKI 风险和随后的 CKD 的影响然后，申请人将检查大规模卫生系统数据库和前瞻性队列研究（目标 1）。使用两种不同的、但互补的方法：开发相互作用的药代动力学模拟模型，然后对相同相互作用的回顾性队列研究（目标 2）将提供对方法的整合的见解。肾脏疾病对 CYP 抑制的影响是单独使用任何一种方法都无法实现的。该提案将对候选人进行肾脏药物流行病学、高级统计模型、和药代动力学模拟，对3500万医院的用药安全具有重要意义这项研究将产生超出特定药物范围的新知识。研究并促进候选人成为肾脏病独立研究者药物流行病学。