Comparison of Drug Availability in the Inner Ear After Oral, Transtympanic, and Combined Administration.

Yang Li,Kaoru Ogawa,Shinsuke Shibata,Masahiro Ozaki,Masaya Nakamura,Sho Kanzaki,Hideyuki Okano

doi:10.3389/fneur.2021.641593

Abstract

Although combination of oral and transtympanic drug therapy (CT) has been proved more effective and safer for idiopathic sudden sensorineural hearing loss (ISSNHL) by some clinical trials, there are few laboratory researches on the pharmacokinetics in the inner ear following CT on account of structural limitations of the inner ear. The aim of the present study was to investigate the pharmacokinetic behaviors of CT in the inner ear of mice. Eighteen transgenic GFAP-Luc mice which express luciferase in cochlear spiral ganglion cells were divided into oral administration (OR) group, transtympanic injection route (TT) group and CT group, and luciferin was delivered into the inner ear of these mice through oral, transtympanic or combined routes, respectively. A new in vivo imaging system was used to observe luciferin/luciferase signals and the compare the pharmacokinetics of different administration routes in the inner ear of mice. Bioluminescence signals were observed in the inner ear 3.3 ± 2.6 min after CT, significantly earlier than that of OR group (15.8 ± 7.4 min). CT owned the longest reaching-peak time and largest area under the curve (AUC) among three groups. Compared to TT, CT had longer biological half-life and higher AUC value, but did not displayed stronger peak value. There were significant differences in the peak values between OR group and TT group and between OR group and CT group. This study suggests that the OR route is less effective than the TT or CT route, and combination of OR and TT can deliver more drugs into the inner ear and confer a longer therapeutic window, but cannot increase drug intensity.

Highlights

Inner ear disorders are major clinical diseases that significantly impact human health
Luciferase kinetics were quantitatively evaluated for the time course in the inner ear (Figure 2) In the OR group, the time when bioluminescence signals could be observed in the inner ear was 15.8 ± 7.4 min, whereas this time was significantly reduced in the transtympanic route of administration (TT) group (4.1 ± 2.0 min) and the CT group (3.3 ± 2.6 min) (P < 0.05 for each; n = 6) (Figure 3A)
Local drug delivery including intratympanic and intracochlear administrations has important advantages to treat inner ear disorders, offering precision of dose and avoidance of possible adverse effects associated with systemic administration [18]

Summary

Introduction

Inner ear disorders are major clinical diseases that significantly impact human health. The effective and safe treatment of these diseases has become increasingly dependent on inner ear drug delivery systems. The transtympanic route of administration (TT) can bypass the BLB and access directly the inner ear through round window membrane, increasing the drug concentration at the targeted organ and reducing the systemic adverse effects. This route requires repeated injections to achieve a prolonged residence in the middle ear and a therapeutic concentration in the inner ear [3, 4]. For better understanding the mechanism of CT, it is very imperative to investigate its pharmacokinetic behaviors, especially the amount of drug reaching the inner ear and its residence time in the inner ear

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