Utility of the auditory brainstem response evaluation in non-clinical drug safety evaluations

Abernathy, Matthew M.; Gauvin, David V.; Tapp, Rachel; Yoder, Jay A.; Baird, Theodore J.

doi:10.1016/j.vascn.2015.05.005

Cited by 8 publications

(6 citation statements)

References 53 publications

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“…This is a very informative paper that reduces study duration and increases efficiency by improving upon non-clinical surgical methods. Abernathy, Gauvin, Tapp, Yoder, and Baird (2015) provide a very interesting review article that highlights the auditory system and the possible impact a drug can have on function. It should be known, and may be surprising, that over 700 drugs (or their combinations) have a potential risk for effects on the human auditory system (Cary, Clarke, & Delic, 1997).…”

Section: Methods Used To Evaluate Cns Function In Spmentioning

confidence: 99%

“…The US FDA requires that such drugs be evaluated with the Auditory Brainstem Response (ABR) (US FDA, 2008). As Abernathy et al (2015) outline, the ABR is an auditory evoked potential that assesses function and drug effects on function by establishing minimum intensity thresholds. These thresholds can then be monitored and changes reflect the impact of dysfunction that develops with drug administration.…”

Section: Methods Used To Evaluate Cns Function In Spmentioning

confidence: 99%

See 1 more Smart Citation

The shifting landscape of safety pharmacology in 2015

Authier¹,

Stonerook

Curtis

2015

Journal of Pharmacological and Toxicological Methods

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Section: Methods Used To Evaluate Cns Function In Spmentioning

confidence: 99%

Section: Methods Used To Evaluate Cns Function In Spmentioning

confidence: 99%

The shifting landscape of safety pharmacology in 2015

Authier¹,

Stonerook

Curtis

2015

Journal of Pharmacological and Toxicological Methods

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“…ABR assessments are often performed during GLP ototoxicity studies and are part of the FDA Guidelines. This practice is understandable, as ABR is a valid and reliable preclinical assessment of auditory function ( Abernathy et al, 2015 ) and is among the few measures that can be effectively translated to human.…”

Section: Ototoxicity Monitoring During Non-clinical Phasementioning

confidence: 99%

Ototoxicity: a high risk to auditory function that needs to be monitored in drug development

Pasdelou,

Byelyayeva,

Malmström

et al. 2024

Front. Mol. Neurosci.

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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.

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“…This test is used to measure otoacustic emissions, or OAEs, which are sounds given off by the sensory (hair cells) cells located in the inner ear when responding to sound [ 18 ]. These auditory tests are used for newborn hearing screening in humans and are also applicable to animals because of the objective, quantitative and non-invasive nature of these tests [ 19 – 21 ]. We have used both tests for the first time in the ABSL4 level facility, to achieve comprehensive analysis of the auditory function in LASV-infected mice.…”

Section: Introductionmentioning

confidence: 99%

CD4 T-cell depletion prevents Lassa fever associated hearing loss in the mouse model

et al. 2022

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Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.

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Utility of the auditory brainstem response evaluation in non-clinical drug safety evaluations

Cited by 8 publications

References 53 publications

The shifting landscape of safety pharmacology in 2015

The shifting landscape of safety pharmacology in 2015

Ototoxicity: a high risk to auditory function that needs to be monitored in drug development

CD4 T-cell depletion prevents Lassa fever associated hearing loss in the mouse model

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