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

• 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
• 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

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.

用挽救生命的氨基糖苷（AG）抗生素治疗的患者可能会遭受不利的副作用 耳毒性 - 永久性听力损失和言语交流退化。我们有关键的差距 了解个人对耳毒性的敏感性，并获得识别有效测试的有效测试 较高的风险。该提案的目的是确定Ag抗生素对听觉功能的影响 与囊性纤维化患者中药物暴露的单个测量有关。我们的长期目标是设计 改善了听觉监测方案，以防止因患者的耳毒性而导致听力防御措施 抗生素。该项目将评估使用扩展高频检测耳毒性发作的新方法 （EHF）内耳功能的测试 - 相对于噪声（OAE）和数字（DIN）的数字（oaes） 个性化药代动力学/动力学（PK/PD）药物暴露的测量。囊性纤维化（CF）是最大的 普遍威胁生命的遗传疾病，并导致童年时期持续的肺部感染 用Ag抗生素治疗，因此是针对预防耳毒性的重要人群。这 纵向观察研究将包括接受AG抗生素治疗治疗的CF患者，并对照 不接受AG的人，其中一半也有CF。我们的假设是这些新发展 听觉测试可以尽早检测到耳毒性，并与PK/PD模型有关。此外，我们假设 PK/PD模型可以预测耳毒性的风险。目前，大多数有风险的患者未经监测耳毒性。 听力损失，主要是由于缺乏可用性和对早期检测方法的认识，以及 可以保留听力的治疗替代方法。可以自动化或通过远程交付的测试 互联网或通过智能手机可以从根本上改善对耳毒性监测的访问。提议 纵向观察设计具有影响力，因为它将提供高度翻译的听觉数据 进行药物暴露的高级测量。临床相关的目标将：（1）随着时间的推移评估关系 在累积剂量的AG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 和耳鸣； （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 检测耳毒性的存在； （3）开发一种临床PK/PD工具来预测Ag耳毒性（变化 与CF患者的AG组织积累有关的听力测定法，DIN或OAE）。预期的结果将 具有重要的积极影响，因为它们将更好地了解耳毒性机制， 可以转化为改进监控的时间和风险因素。未来的基因组研究和临床 通过这种扩展的知识和改善的可用性，可以为保护内耳的试验做准备 诊断和监测工具。