Pharmacokinetics, Safety, and Efficacy of High-Concentration Intratympanic Dexamethasone for Sudden Sensorineural Hearing Loss: An Integrated Non-Human Primate and Clinical Study.

Intratympanic (IT) corticosteroid therapy is a well-established intervention for sudden sensorineural hearing loss (SSNHL), yet its optimal dosing remains undefined. This study aimed to conduct an integrated preclinical and clinical evaluation of high-concentration IT dexamethasone phosphate (Dex-P), focusing on pharmacokinetics (PK), safety, and preliminary efficacy. The study comprised three parts. Part A and Part B evaluated the perilymph and plasma PK of cynomolgus monkeys. Part C assessed the plasma PK, safety, and hearing recovery of standard treatment-failure SSNHL patients following three IT injections of Dex-P (20 or 40 mg/mL, q3d). Preclinical PK data demonstrated the superiority of IT treatment, achieving high and sustained drug levels in the perilymph that were not detected via systemic administration. High-concentration IT injection led to disproportionate increase in perilymph exposure relative to the dose increment, while the corresponding plasma exposure was approximately following the dose proportionality. In SSNHL patients, high-concentration IT administration was well-tolerated with no dose-limiting toxicity. Systemic exposure increased approximately in proportion to the dose increment, and no significant accumulation was observed. Hearing improvement was modest. Although not statistically significant, a greater pure-tone average improvement was observed in the 40 mg/mL group (5.69 dB) compared to the 20 mg/mL group (3.06 dB). High-concentration IT Dex-P (up to 40 mg/mL) is a feasible and safe option for the salvage treatment of SSNHL. The trend toward better hearing outcomes, combined with its enhanced local target-site exposure and favourable safety profile, provides a rationale for further investigation in larger, controlled clinical trials to optimize therapeutic efficacy.