Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination

Sanketh S Moudgalya,Kevin Wilson,Xiaoxia Zhu,Mikalai M Budzevich,Joseph P Walton,Nathan D Cahill,Robert D Frisina,David A Borkholder

doi:10.1016/j.heares.2019.05.009

Abstract

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Highlights

Current and future treatments of inner ear disorders such as sensorineural hearing loss [1], Ménière’s disease [2] and genetic diseases require local delivery of restorative and protective compounds to the inner ear
The intensity values inside the scala are different for the atlas and the scan owing to their different imaging modalities
The region outside the cochlea is empty in the atlas, whereas it is filled with various tissues in the scans resulting in lower Jaccard index

Summary

Introduction

Current and future treatments of inner ear disorders such as sensorineural hearing loss [1], Ménière’s disease [2] and genetic diseases require local delivery of restorative and protective compounds to the inner ear. Direct methods for measuring drug concentrations are based on measuring a specific ion (e.g.: trimethylphenylammonium) using ion-selective micro-electrodes [6], or by drawing minute perilymph samples from the basal [7, 8] or apical turns [9, 10] of the cochlea or from the vestibular canals [11, 12]. These methods are limited in their spatio-temporal resolution and are difficult to employ in animals smaller than the guinea pig. There remains a need for advanced methods to monitor drug concentrations within the three cochlear scalae over time that provide enhanced spatial resolution and are suitable for a broad range of infused compounds and animal species, including the genetically-mapped murine model system

Results

Discussion

Conclusion