Investigation of inner ear drug delivery with a cochlear catheter in piglets as a representative model for human cochlear pharmacokinetics

Abstract

Hearing impairment is the most common sensory disorder in humans, and yet hardly any medications are licensed for the treatment of inner ear pathologies. Intricate pharmacokinetic examinations to better understand drug distribution within this complex organ could facilitate the development of novel therapeutics. For such translational research projects, animal models are indispensable, but differences in inner ear dimensions and other anatomical features complicate the transfer of experimental results to the clinic. The gap between rodents and humans may be bridged using larger animal models such as non-human primates. However, their use is challenging and impeded by administrative, regulatory, and financial hurdles. Other large animal models with more human-like inner ear dimensions are scarce. In this study, we analyzed the inner ears of piglets as a potential representative model for the human inner ear and established a surgical approach for intracochlear drug application and subsequent apical sampling. Further, controlled intracochlear delivery of fluorescein isothiocyanate-dextran (FITC-d) was carried out after the insertion of a novel, clinically applicable CE-marked cochlear catheter through the round window membrane. Two, six, and 24 hours after a single injection with this device, the intracochlear FITC-d distribution was determined in sequential perilymph samples. The fluorometrically assessed concentrations two hours after injection were compared to the FITC-d content in control groups, which either had been injected with a simple needle puncture through the round window membrane or the cochlear catheter in combination with a stapes vent hole. Our findings demonstrate not only significantly increased apical FITC-d concentrations when using the cochlear catheter but also higher total concentrations in all perilymph samples. Additionally, the concentration decreased after six and 24 hours and showed a more homogenous distribution compared to shorter observation times.

Evaluation of intracochlear pressure and distribution during fluid application in cochlea models and human petrous bone

“…In our study, the measurement of substance distribution was performed through visual evaluation. Previously, study groups, that evaluated the intracochlear substance injection and distribution evaluated the distribution by the concentration of makers such as polysaccharide fluorescein isothiocyanate dextran (FITC-d) or trimethylphenylammonium (TMPA) (21, 11). In the Future, the measurement through mass spectrometry or gas or liquid chromatograph could deliver more precise information pharmacokinetically.…”

“…The design of those experiments differs in terms of approach, material or sampling method. In this sense, injections into the perilymph have been performed via needles (8,9), glass pipettes (10), cochlear catheters (CC) (11) and even during the cochlear implantation (12,13). With intracochlear injection, the distribution of substance along the scala tympani was effective.…”

Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL

“…To avoid interference with cisplatin’s antitumor activity at the tumor site, ototoxicity-preventing drugs should ideally be applied locally via intratympanic or intracochlear administration. 31 , 32 , 33 , 34 However, since chemotherapy often involves several cycles of treatment, repeated administration of antiototoxic drugs is required, which is invasive and could cause adverse local reactions, such as inflammation. 35 Furthermore, the short half-life of antiototoxic drugs ranging from 15 min to 5.5 h could limit the therapeutic effect within the cochlea.…”

Deep intracochlear injection of triamcinolone-acetonide with an inner ear catheter in patients with residual hearing

“…For more sustained drug release, drug-eluting electrodes or electrodes connected to a catheter and an osmotic pump enable an intrascalar delivery up to the medial turn of the cochlea ( Plontke et al, 2017 ; Manrique-Huarte et al, 2020 ; Dhanasingh and Hochmair, 2021 ). Another method to provide the cochlea locally with drugs prior to cochlear implantation is the use of an inner ear catheter as a drug delivery device ( Prenzler et al, 2018 ; Yildiz et al, 2023 ). It has been successfully used for glucocorticoid delivery in preclinical models for preservation of residual hearing ( Ibrahim et al, 2010 ; Ibrahim et al, 2011 ).…”

“…Until now, this had not been possible either through systemic or any other local drug delivery strategy. However, this approach requires the insertion of the catheter to the cochlea and a subsequent second insertion of the electrode array ( Prenzler et al, 2018 ; Yildiz et al, 2023 ). There have been concerns rising that this procedure may not be suitable for patients with residual hearing since it may increase the risk of loss of residual hearing due to additional mechanical trauma by the catheter insertion.…”