PDF(Pubmed)
Abstract：
Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field - required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use - ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.
摘要：
听力损失是全球主要的健康问题，影响全球约15亿人。它的发病率正在大幅上升，有人预测到2050年，全球四分之一的人口将经历不同程度的听力缺陷。环境因素，如老化，暴露在巨大的噪音中，耳毒性药物的摄入与获得性听力损失的发生有关。导致内耳损伤的耳毒性是全球获得性听力损失的主要原因。这可以通过在药物开发的临床前阶段早期测试听力功能来最小化或避免。虽然耳毒性的评估对于听力领域的候选药物是明确的-通过耳途径给药并预期在临床使用期间到达中耳或内耳的药物是必需的-耳毒性测试不需要用于所有其他治疗领域。不幸的是,这导致了200多种耳毒性药物的销售。本出版物的目的是提高对药物引起的耳毒性的认识，并根据现有指南和自己的经验制定一些建议。耳毒性测试程序应适应治疗类型，其适应症（针对耳朵或可能具有耳毒性的其他药物类别的一部分），以及要测试的资产数量。对于多分子和/或多剂量，筛选选项是可用的：体外（耳细胞测定），离体（耳蜗外植体），和体内（斑马鱼）。在评估候选药物的耳毒性时，将其耳毒性与类似类别的著名对照药物进行比较是很好的做法。筛选测定法提供了一种流线型和快速的方法来了解药物对于内耳结构是否通常是安全的。哺乳动物动物模型提供了药物耳毒性的更详细的表征，有可能使用功能定位和量化损伤，行为，和形态学读出。通常进行补充组织学测量，特别是用耳蜗图量化毛细胞损失。耳毒性研究可以在啮齿动物(小鼠，大鼠),豚鼠和大型物种。然而,在事业上,或者至少尝试，同一物种内的所有临床前研究，至关重要。这包括从药代动力学和药理学功效研究开始，并延伸到毒性研究。生活中的读数包括听觉脑干反应（ABR）和失真产品耳声发射（DPOAE）测量，评估感觉细胞和听觉神经的活性和完整性，反映感觉神经性听力损失。准确,可重复,和高通量ABR措施是这些临床前试验的质量和成功的基础。和人类一样,体内耳镜评估常规进行，以观察鼓膜和耳道。这通常是为了检测炎症的迹象。耳蜗是一种音调结构。毛细胞反应性与位置和频率有关，位于耳蜗顶点附近的毛细胞传导低频，而位于基部的毛细胞传导高频。耳蜗图旨在量化整个耳蜗的毛细胞，从而确定与特定频率相关的毛细胞损失。然后将该测量与ABR&DPOAE结果相关联。耳毒性评估评估候选药物对听觉和前庭系统的影响，降低听力损失和平衡障碍的风险，定义一个安全剂量,优化治疗效益。这些类型的研究可以在治疗解决方案的早期开发期间开始，ABR和耳镜评估。根据化合物的作用机理，研究可包括DPOAE和耳蜗图。在后来的发展中，GLP（良好实验室规范）耳毒性研究可能需要基于耳部相关给药途径，目标,或已知潜在的耳毒性。
