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

Area of Science:

• Ototoxicology
• Pharmacology
• Drug Development

Background:

• Hearing loss affects 1.5 billion globally, projected to reach 25% by 2050.
• Acquired hearing loss is often caused by aging, noise exposure, and ototoxic medications.
• Ototoxicity, leading to inner ear damage, is a significant cause of acquired hearing loss.

Purpose of the Study:

• To raise awareness of drug-induced ototoxicity.
• To provide recommendations for adapted ototoxicity testing programs.
• To highlight the importance of early hearing function assessment in preclinical drug development.

Main Methods:

• Screening options include in vitro (cell assays), ex vivo (cochlear explant), and in vivo (zebrafish) models.
• Mammalian animal models (rodents, guinea pigs) offer detailed characterization using functional, behavioral, and morphological readouts.
• In vivo assessments include Auditory Brainstem Response (ABR), Distortion Product OtoAcoustic Emissions (DPOAE), and cochleograms to quantify hair cell loss.

Main Results:

• Ototoxicity testing is not universally required, leading to over 200 ototoxic marketed drugs.
• Screening assays rapidly identify potential inner ear safety concerns.
• Mammalian models allow for precise localization and quantification of drug-induced damage.

Conclusions:

• Ototoxicity testing programs should be tailored to therapy type, indication, and drug candidate volume.
• Comparing candidate drug ototoxicity to known controls is good practice.
• Comprehensive preclinical ototoxicity assessments are vital for de-risking hearing loss and balance disorders, defining safe drug doses, and optimizing therapeutic benefits.