耳毒性:药物开发过程中需要监测的听觉功能高风险

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-05-02 DOI:10.3389/fnmol.2024.1379743
Marie-Pierre Pasdelou, Lise Byelyayeva, Susanna Malmström, Sylvie Pucheu, Marie Peytavy, Hugo Laullier, Donald B. Hodges, Abraham R. Tzafriri, Gaëlle Naert
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引用次数: 0

摘要

听力损失是一个重大的全球健康问题,影响着全球约 15 亿人。听力损失的发病率正急剧上升,有人预计到 2050 年,全球四分之一的人口将出现不同程度的听力障碍。后天性听力损失的发病与环境因素有关,如衰老、暴露于高噪音环境和摄入耳毒性药物。耳毒性导致内耳损伤是全球后天性听力损失的主要原因。如果在药物开发的临床前阶段及早检测听力功能,就可以最大限度地减少或避免这种情况的发生。虽然听力领域候选药物的耳毒性评估已经有了明确的规定--通过耳道给药并有望在临床使用中到达中耳或内耳的药物必须进行耳毒性测试,但所有其他治疗领域的药物都不需要进行耳毒性测试。遗憾的是,这导致市场上出现了 200 多种耳毒性药物。本出版物旨在提高人们对药物诱发耳毒性的认识,并根据现有指南和自身经验提出一些建议。耳毒性检测计划应根据治疗类型、适应症(针对耳部或其他可能具有耳毒性的药物类别的一部分)以及需要检测的资产数量进行调整。对于多种分子和/或多种剂量的药物,可选择体外(耳细胞试验)、体外(耳蜗移植)和体内(斑马鱼)筛选。在评估候选药物的耳毒性时,好的做法是将其耳毒性与知名的同类对照药物的耳毒性进行比较。筛选试验提供了一种简化而快速的方法,可用于了解药物对内耳结构是否普遍安全。哺乳动物模型能更详细地描述药物的耳毒性,并能利用功能、行为和形态读数对损伤进行定位和量化。此外,还可通过耳蜗图量化毛细胞的损失。耳毒性研究可在啮齿动物(小鼠、大鼠)、豚鼠和大型动物中进行。然而,在同一物种内进行或至少尝试进行所有临床前研究是至关重要的。这包括从药代动力学和药理学疗效研究开始,一直延伸到毒性研究。生活中的读数包括听性脑干反应(ABR)和失真产物声发射(DPOAE)测量,用于评估感觉细胞和听觉神经的活性和完整性,反映感音神经性听力损失。准确、可重复和高通量的 ABR 测量是这些临床前试验的质量和成功的基础。与人类一样,体内耳镜评估也是观察鼓膜和听道的常规方法。这通常是为了检测炎症迹象。耳蜗是一个音调结构。毛细胞的反应性与位置和频率有关,靠近耳蜗顶端的毛细胞可传递低频,而位于底部的毛细胞则可传递高频。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。然后将这一测量结果与 ABR &amp; DPOAE 结果相关联。耳毒性评估可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失调的风险,确定安全剂量,优化治疗效果。这类研究可在治疗方案的早期开发阶段通过 ABR 和耳镜评估启动。根据化合物的作用机制,研究可包括 DPOAE 和耳蜗图。在研发后期,根据与耳部相关的给药途径、目标或已知的潜在耳毒性,可能需要进行 GLP(良好实验室规范)耳毒性研究。
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Ototoxicity: a high risk to auditory function that needs to be monitored in drug development
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 &amp; 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.
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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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