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Title: Pharmacokinetics and tissue distribution of neurotrophin 3 after intracochlear delivery
Authors: Richardson, Rachael
Hu, Qi-Ying
Shi, Fuxin
Nguyen, Trung
Fallon, James
Flynn, Brianna
Wise, Andrew
Keywords: Neurotrophin-3
Cochlea
Drug delivery
Radiolabel
Clearance
Distribution
Pharmacokinetics
Hearing loss
Issue Date: Feb-2019
Publisher: Elsevier B.V.
Citation: Richardson, R. T., Q. Y. Hu, F. Shi, T. Nguyen, J. B. Fallon, B. O. Flynn, and A. K. Wise. 2019. Pharmacokinetics and tissue distribution of neurotrophin 3 after intracochlear delivery. Journal of controlled release : official journal of the Controlled Release Society: [epub ahead of print].
Abstract: Neurotrophin therapy has potential to reverse some forms of hearing loss. However, cochlear pharmacokinetic studies are challenging due to small fluid volumes. Here a radioactive tracer was used to determine neurotrophin-3 retention, distribution and clearance after intracochlear administration. (125)I-neurotrophin-3 was injected into guinea pig cochleae using a sealed injection technique comparing dosing volumes, rates and concentrations up to 750 mug/mL. Retention was measured by whole-cochlea gamma counts at five time point while distribution and clearance were assessed by autoradiography. Smaller injection volumes and higher concentrations correlated with higher retention of neurotrophin-3. Distribution of neurotrophin-3 was widespread throughout the cochlear tissue, decreasing in concentration from base to apex. Tissue distribution was non-uniform, with greatest density in cells lining the scala tympani and lower density in neural target tissue. The time constant for clearance of neurotrophin-3 from cochlear tissues was 38h but neurotrophin-3 remained detectable for at least 2 weeks. Neurotrophin-3 was evident in the semi-circular canals and minor spread to the contralateral cochlea. This study is the first comprehensive evaluation of the disposition profile for a protein therapy in the cochlea. The findings and methods in this study will provide valuable guidance for the development of protein therapies for hearing loss.
URI: http://repository.bionicsinstitute.org:8080/handle/123456789/338
ISSN: 0168-3659
Appears in Collections:Bionic Hearing Research Publications

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