Inner ear distribution of the small, lipophilic pyridoindole AC102 after intratympanic drug delivery

Hearing loss represents a major global health burden, affecting one in five people worldwide. Pharmaceutical treatment options remain scarce, and efficient drug delivery to the inner ear is challenging. Systemic administration is limited by the inner ear’s low blood supply and the restrictive blood-labyrinth barrier. Local administration into the middle ear increases inner ear drug concentrations while minimizing systemic side effects. However, few otoprotective drugs for local delivery are currently under investigation. AC102, a small lipophilic pyridoindole, has shown preclinical efficacy in attenuating hearing loss after noise trauma and cochlear implantation following application as a thermosensitive hydrogel. Its pharmacokinetics, however, remain unexplored. This study investigated AC102’s molecular properties, and evaluated its concentration and distribution within cochlear fluid and tissue after local application over 24 hours. AC102s pharmacokinetics were evaluated in the guinea pig and subsequently in a large animal model with human-like inner ear anatomy, the pig. AC102 was found to rapidly diffuse into and evenly distribute within the cochlear perilymph following local intratympanic application. The compound quickly accumulated in the cochlea and neural tissues, while systemic drug levels remained comparably low. Moreover, our comparison revealed a marked difference of AC102 concentrations between the guinea pig, the pig, and predictions based of computational models. These findings provide insights into the distribution of atypical small lipophilic molecules such as AC102 after local application and emphasize the need for quantify tissue drug concentrations. Moreover, these results underline the need for caution in currently utilized predictions of cochlear drug distribution, which mainly focus on perilymph drug concentrations and computational modelling. • AC102 reaches high intracochlear concentrations following local intratympanic application. • AC102 accumulates within cochlear and neural tissues. • Inner ear tissue collection is essential to study cochlear drug delivery. • The pig represents a highly suitable animal model to study cochlear pharmacokinetics. • A great discrepancy between in-vivo and simulation models was observed.