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

项目摘要/摘要 接受氨基糖苷类(AG)抗生素治疗的患者可能会出现以下不良反应 耳毒性-永久性听力损失和语言交流能力下降。我们的业务存在严重差距 了解个体对耳毒性的易感性，并获得有效的测试，以确定那些 风险更高。本建议的目的是确定AG抗生素对儿童听功能的影响。 囊性纤维化患者个体药物暴露措施的关系。我们的长期目标是设计 改进的听觉监测方案预防服用AG患者耳毒性所致的听力障碍 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)内耳功能测试-耳声发射(OAEs)和噪声中的位数(DIN)，与 药物暴露的个体化药代动力学/动力学(PK/PD)措施。囊性纤维化(CF)是最常见的 常见的危及生命的遗传病，并导致儿童时期持续的肺部感染，这些感染经常是 因此，使用AG抗生素治疗是预防耳毒性的重要目标人群。这 纵向观察研究将包括接受AG抗生素治疗的CF患者和对照组 未接受AGs治疗的人，其中一半人也患有CF。我们的假设是，这些新发展出来的 听力测试可以早期发现耳毒性，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的可用性和认识，以及 可以保护听力的治疗替代方案。测试可以自动化，也可以通过 通过互联网或智能手机可以从根本上改善对耳毒性监测的获取。建议数 纵向观察设计是有影响力的，因为它将提供高度可翻译的听觉数据 到先进的药物暴露措施。临床上相关的目标将：(1)随着时间的推移评估关系 在AGs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 和耳鸣；(2)将耳声发射测试与听力损失转移进行比较，并确定哪一种测试更准确 检测耳毒性的存在；(3)开发临床PK/PD工具来预测AG耳毒性(变化 听力测试、DIN或OAE)与CF患者AG组织蓄积的关系。预期的结果将是 有重要的积极影响，因为它们将提供更好的了解耳毒性机制， 可转化为改进监测的时机和风险因素。未来的基因组研究和临床 保护内耳的试验将通过这种扩展的知识和改进的可获得性来促进 诊断和监控工具。

PROJECT SUMMARY/ABSTRACT 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.