Prevention of Ototoxicity with Effective Monitoring (POEM) Pharmacokinetic and Auditory Linkages

通过有效监测 (POEM) 药代动力学和听觉联系来预防耳毒性

基本信息

批准号：
10684143
负责人：
Martin Patrick Feeney
金额：
$ 63.42万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684143
关键词：
Address Adverse event Affect Aminoglycoside Antibiotics Aminoglycosides Antibiotic Therapy Antibiotics Assessment tool Auditory Bacterial Infections Behavioral Blood Cellular Phone Childhood Clinical Clinical Data Clinical Trials Collaborations Communication Consumption Creativeness Critical Illness Cystic Fibrosis Data Diagnostic Diagnostic tests Digit structure Dose Drug Exposure Drug Kinetics Early Diagnosis Effectiveness Follow-Up Studies Fostering Frequencies Future Genetic Genetic Diseases Genomics Goals Guidelines Health Hearing Hearing Tests High-Frequency Hearing Loss Human Improve Access Individual Individual Differences Infection Inner Hair Cells Internet Knowledge Labyrinth Life Link Longitudinal, observational study Lung infections Measures Methods Modeling Monitor Noise Oregon Outcome Outcome Study Outer Hair Cells Patient Self-Report Patients Pediatric Hospitals Persons Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacotherapy Phenotype Physicians Physiological Population Predisposition Prevention Prevention trial Protocols documentation Public Health Pure-Tone Audiometry Reporting Research Risk Risk Factors Science Sensorineural Hearing Loss Speech Synapses Testing Time Time Factors Tinnitus Tissues Translating United States National Institutes of Health Universities alertness alternative treatment aminoglycoside-induced ototoxicity antimicrobial auditory threshold shift behavioral response clinically relevant cohort cystic fibrosis patients design detection method dosage early awareness hearing impairment hearing preservation high risk improved innovation nephrotoxicity neural neural hearing loss novel otoacoustic emission ototoxicity permanent hearing loss preservation prevent prevent hearing loss programs prospective remote delivery response risk prediction side effect tool uptake young adult

项目摘要

Patients treated with life-saving aminoglycoside (AG) antibiotics may experience adverse side effects of ototoxicity – permanent hearing loss and degraded speech communication. There are critical gaps in our understanding of individual susceptibility for ototoxicity, and access to effective tests that identify those at higher risk. The objective of this proposal is to determine the effect of AG antibiotics on auditory function in relation to individual measures of drug exposure in patients with cystic fibrosis. Our long-term goal is to design improved auditory monitoring protocols to prevent hearing deficits due to ototoxicity in patients taking AG antibiotics. This project will evaluate new methods to detect onset of ototoxicity using extended high frequency (EHF) tests of inner ear function – otoacoustic emissions (OAEs) and digits in noise (DIN), in relation to individualized pharmacokinetic/dynamic (PK/PD) measures of drug exposure. Cystic fibrosis (CF) is the most common life-threatening genetic disease and causes persistent lung infections in childhood that are frequently treated with AG antibiotics, thus is an important population to target for prevention of ototoxicity. This longitudinal observational study will include CF patients treated with AG antibiotic treatments, and control persons not treated with AGs, half of whom also have CF. Our hypothesis is that these newly developed auditory tests can detect ototoxicity early and are related to the PK/PD models. Further, we hypothesize that PK/PD models can predict risk for ototoxicity. Currently, most patients at risk are not monitored for ototoxic hearing loss, primarily due to lack of availability and awareness of early detection methods, as well as treatment alternatives that can preserve hearing. Tests that can be automated or delivered remotely via the internet or through smartphones could fundamentally improve access to ototoxicity monitoring. The proposed longitudinal observational design is impactful because it will provide highly translatable auditory data in relation to advanced measures of drug exposure. The clinically relevant aims will: (1) Assess relationships over time between cumulative doses of AGs, shifts in EHF pure tone and DIN tests, and self-reported hearing difficulty and tinnitus; (2) Compare OAE tests to hearing loss shifts and determine which OAE test is more accurate to detect presence of ototoxicity; (3) Develop a clinical PK/PD tool to predict AG ototoxicity (change in audiometry, DIN or OAEs) in relation to AG tissue accumulation in CF patients. The expected outcomes will have important positive impacts because they will provide a better understanding of ototoxicity mechanisms, timing and risk factors that can be translated into improved monitoring. Future genomic studies and clinical trials to protect the inner ear would be facilitated by this expanded knowledge and by availability of improved diagnostic and monitoring tools.

使用挽救生命的氨基糖苷类 (AG) 抗生素治疗的患者可能会出现不良副作用耳毒性——永久性听力损失和言语交流能力下降。了解个体对耳毒性的易感性，并获得有效的测试来识别那些该提案的目的是确定 AG 抗生素对听觉功能的影响。与囊性纤维化患者药物暴露的个体测量的关系我们的长期目标是设计。改进听觉监测方案，以防止服用 AG 的患者因耳毒性而导致听力缺陷该项目将评估使用扩展高频检测耳毒性发作的新方法。 (EHF) 内耳功能测试 – 耳声发射 (OAE) 和噪声中的数字 (DIN)，与药物暴露的个体化药代动力学/动力学（PK/PD）测量是最重要的。常见的危及生命的遗传病，并导致儿童期持续性肺部感染，这种感染经常发生因此，AG 抗生素是预防耳毒性的重要目标人群。纵向观察研究将包括接受 AG 抗生素治疗的 CF 患者和对照未接受 AG 治疗的人，其中一半也患有 CF。听觉测试可以早期发现耳毒性，并且与 PK/PD 模型相关。 PK/PD 模型可以预测耳毒性风险。目前，大多数有风险的患者没有接受耳毒性监测。听力损失，主要是由于缺乏早期检测方法和意识，以及可以保留听力的治疗替代方案，可以通过自动化或远程进行。互联网或通过智能手机可以从根本上改善耳毒性监测的可及性。观察设计是有影响力的，因为它将提供相关的高度可翻译的听觉数据药物暴露的高级测量方法的临床相关目标将： (1) 评估随时间的关系。 AG 的累积剂量、EHF 纯音和 DIN 测试的变化以及自我报告的听力困难之间的关系 (2) 将 OAE 测试与听力损失变化进行比较，并确定哪种 OAE 测试更准确检测是否存在耳毒性；（3）开发临床 PK/PD 工具来预测 AG 耳毒性（变化）听力测定、DIN 或 OAE）与 CF 患者 AG 组织积累相关。具有重要的积极影响，因为它们将使人们更好地了解耳毒性机制，可以转化为改进的未来基因组研究和临床的时间和风险因素。扩大的知识和改进的可用方法将有助于保护内耳的试验诊断和监控工具。