Purchase this article with an account.
Timothy W Olsen, Timothy Wiedmann, Roy Dyer, Daniel Paley, Kathy Wabner, Jenn Schmit, Jana Sellers, Ju Byung Chae, Ravinder Singh, Micah A Chrenek, Jeffrey H Boatright; A Pharmacokinetic Analysis of a Biodegradable Suprachoroidal Sustained Drug Delivery Device for the Bile Acid Tauroursodeoxycholic Acid in the Porcine Model. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3276.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To determine the drug tissue levels of tauroursodeoxycholic acid (TUDCA) in the pig model when delivered orally, intravenously (IV), intravitreally (Ivit), and from a suprachoroidal, sustained release devices (SCD-L or SCD-H).
Over 615 individual tissue or serum specimens from 53 pigs were analyzed. TUDCA was delivered using: oral (n=8), IV (n=6), Ivit (n=12), SCD-L (n=16) and SCD-H (n=16) and compared to two untreated control animals (4 eyes). Suprachoroidal TUDCA was formulated into a biodegradable suprachoroidal sustained release wafer. Serum and/or dissected tissue specimens were immediately frozen and obtained at 5, 30, and 60 minutes after IV dosing; 8 hours, 1, 2, and 6 days after po dosing, and 1, 2, and 4 weeks after SCD sustained-release delivery. Tissue specimens included: Macular retina, macular choroid, peripheral retina and peripheral choroid. TUDCA and bile acid metabolites were extracted in ethanol, clarified, and dried under N2 gas. Dried extract was hydrated in methanol, and a portion was mixed with deuterium-labeled TUDCA for analysis using HPLC tandem mass spectrometry. Concentrations were normalized relative to either tissue total protein or cholesterol.
The highest tissue levels were consistently found in the peripheral choroid, immediately over the wafer (p<0.001) with the next highest levels were in the remaining peripheral choroid (p<0.001) and peak SCD drug tissue levels at day 6 (p<0.001). There were variable TUDCA levels in the macular choroid, macular and peripheral neurosensory retina. The fellow, untreated eye had elevated choroidal TUDCA levels, suggesting systemic delivery from the SCD. Serum levels remained elevated at 4 weeks with the SCD devices, peaked at 2 days after oral dosing, and 30 minutes following IV delivery.
We have characterized and quantified TUDCA and metabolite ocular tissue levels following oral, IV, Ivit, and suprachoroidal delivery. The highest local tissue levels were obtained immediately adjacent to the SCD implant. Data has important implications for local and systemic ophthalmic drug delivery pharmacokinetics.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only