Estudio de la farmacocinética coclear por medio de la liberación de fármaco a través de un implante coclear en un modelo experimental animal: Macaca fascicularis

Resum

At present, the cochlear implant (CI) is one of the most widely used devices to treat severe-to-profound sensorineural hearing loss. Despite improvements in surgical technique and electrode arrays, its placement leads to damage to the inner ear, as well as a pro-inflammatory environment that favours increased electrical impedances and worsens postoperative hearing outcomes. Recent animal experimentation reveals that intracochlear corticosteroid administration would decrease the formation of the fibrotic layer around the electrode post-implantation, which would enhance CI performance. Given that the cochlea is a relatively isolated organ in the body, systemic administration of drugs to treat auditory impairment has failed to yield satisfactory results thus far. Furthermore, intratympanic treatments have a limited long-term therapeutic eect. Therefore, the possibility of using a treatment based on the association of a CI with drugs or gene therapy has been explored in recent decades. To this end, a new CI device with a cannula-associated delivery pump was developed that would make it possible to treat hearing loss through a combined approach of drug therapy and electrical stimulation. However, the pharmacokinetics of cochlear fluids have yet to be fully understood. A suitable knowledge of drug behaviour and distribution within the inner ear would provide insight into the precise impact of drug administration, ensuring long-term treatment, eective dosage control, and the possibility of using a variety of drugs. Given the satisfactory findings in other experimental animals and the recent studies that demonstrate the anatomical and physiological similarity between primates and humans, the translation to experimentation in Macaca fascicularis (Mf) would enable the results obtained in the future to be extrapolated to humans, with the aim of gaining in-depth knowledge regarding the pharmacokinetic characteristics of the human cochlea, thereby establishing useful doses and therapies with fewer side eects to treat dierent auditory pathologies. Thus, the main objective of this doctoral thesis is to establish the existing fluid dynamics of the cochlea in an experimental animal model: Mf, evidencing the existence of a flow in the apical direction, assisted by dierent intracochlear factors and also conditioned by them. This study was conducted according to the basic principles governing pharmacokinetics: the LADME (Liberation, Absorption, Distribution, Metabolism, and Elimination) scheme. A prospective, longitudinal, experimental and comparative study was performed in a total of 15 Mf implanted with a preclinical device, CI Electrode Array HL14DD, manufactured by Cochlear Ltd., associated with a release pump loaded with fluorescein isothiocynate, associated with dextran (FITC-Dextran). Three groups (5 Mf each) were formed based on the scheduled release time: Group 2 hours, Group 24 hours and Group 7 days. Perilymph samples (10 samples, 1 µL each) were taken from the cochlear apex and analysed immediately afterwards by spectrofluorimeter. After euthanasia of the animal, a detailed histological analysis of the implanted temporal bone was conducted. The results were analysed, interpreted, and compared with each other, as well as with findings from previous studies in other experimental animals. These results support the viability of the Mf as a model to study inner ear pharmacokinetics, with a cochlear flow in the Mf towards the apex, as well as the need for an infusion time of between 2 and 24 hours to attain peak concentrations in the apex. Then, after a period of at least 24 hours to 7 days of substance release, concentrations tend to decrease, corresponding to the beginning of the “washout” period of the substance administered intracochlearly. Furthermore, it is suggested that the anatomical variations in Mf and the existence of possible reservoirs generated as a result of communications between the scala tympani and the extracellular spaces (modiolar space, endolymphatic sinus) could play an important role in maintaining concentrations throughout the sampling period. Major inroads into imaging techniques, as well as the encouraging results obtained in this study, promote new avenues of research, applying these findings to other regions of the inner ear. Minimally invasive techniques to approach the posterior labyrinth would not only enable us to broaden our knowledge regarding local delivery of drugs directly to the inner ear, but also to establish new treatments that would provide a comprehensive approach to the range of conditions that can compromise the proper functioning of this sensory organ, both at the auditory and vestibular levels.