Oct 2019 Charles River Laboratories
Charles River study explains why kidney function tests are a valuable biomarker for hearing loss
Nobody swallows a pill thinking it might harm their hearing. But the truth is, over 100 drugs deemed “safe and effective” by the FDA do affect the inner ear. So why aren’t regulators doing more to integrate auditory studies into the testing of old and new drugs? That is essentially the central point of a review article published recently by scientists from Charles River’s Mattawan facility in Michigan, which specialises in ototoxicity — “science-speak” for the harmful effects to the ear, especially the cochlear or auditory nerve, caused by drugs and other products. The paper makes the case that when biomarkers of kidney toxicity are detected during the early phases of safety assessment studies, they rightfully send up a red flag that supplemental ear function studies should be considered. Ostensibly there appears to be little connection to the organ we hear with and the organ that filters our waster products.
In fact, studies dating back 20 years found a striking association between the hair cells of the inner ear and the proximal tubules in the kidney—specialised structures that re-absorb good molecules, like glucose and minerals, and return them to the bloodstream. Both have common cellular susceptibilities following therapeutic doses of certain classes of drugs, including antibiotics, some cancer drugs and the erectile dysfunction drug Viagra. “While the function and purpose of the inner ear and kidney are different, most of the genes encoding the epithelial transporters or channels in the inner ear are similarly expressed and sensitive to pharmacological interventions in renal tubular transport,” the authors of the paper note.
The Mattawan study, led by David Gauvin, PhD, argues that the tiered testing system now used to determine any adverse effects of a drug needs to integrate auditory function tests earlier in the process. They suggest that the earliest detection of biomarkers of kidney toxicity may also be predictive of ototoxocity. The “early warning” may provide an opportunity to minimise drug-related hearing loss.
Briefly, what is the most important distinction between Tier 1 and Tier 2 testing?
DG: Tier I testing focusses on a “shot gun” approach to the study designs and extracting all available evidence from the Tier I data to answer one simple question, “do we know enough” Tier II studies are initiated if some Tier I data may suggest that an ancillary system may be unduly affected by the doses administered in the Tier I assays that may need further studies. The tiered system is designed to save drug development costs and reduce the total number of purpose bred animals used in the process. If Tier I assays are negative, we move forward. If something in Tier I assays suggest a confound, then Tier II assays are discussed, designed and conducted, so as not to go forward without elucidating what or how that confound may jeopardise clinical advancement of the drug.
Why hasn’t auditory function testing been included in IND-preclinical package?
DG: The ear is a sensory pathway neglected in the tissue list of all tox protocols because of its unique position in the head, the need for specialised post-life processing (decalcification of the bone that protects the organs) and adds time to the reporting timeline, as well.
Your ototoxicity studies cities adverse auditory effects from cancer drugs (cisplatin) and drugs for genetic disorders (Alport). Are their particular classes of drugs that should be red flags for auditory function tests?
DG: That’s a great question. It’s all about benefit – risk analysis. We do know that certain chemotherapeutics cause auditory damage, but the value of these drugs to maintain life outweigh the loss of hearing. Same holds true about aminoglycoside antibiotics – as new agents come to the preclinical arena, these two classes of compounds are generally recommended to include otototoxity, however, new drugs, like Viagra (Sildenafil) were found to be ototoxic only after the drug was approved for licensure. To the man that has cardiac disease or diabetes, the effects of Viagra on restoring sexual performance outweighs any changes in cochlear function. It is always about clinical utility and patient well-being.
What is the most important take home message from this study?
DG: We have learned our lesson from Viagra – we did not know enough about Viagra’s influence on hearing prior to drug approval. Were there early biomarkers for this potential that were overlooked? The simple addition of recently validated biomarkers in urine and blood to early tox studies may prevent the unexpected finding of “hearing loss” following drug approval. Hearing loss is more than a nuisance, it is a quality of life issue