July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
A Pharmacokinetic Analysis of a Biodegradable Suprachoroidal Sustained Drug Delivery Device for the Bile Acid Tauroursodeoxycholic Acid in the Porcine Model
Author Affiliations & Notes
  • Timothy W Olsen
    Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Timothy Wiedmann
    University of Minnesota, Minnesota, United States
  • Roy Dyer
    Mayo Clinic, Minnesota, United States
  • Daniel Paley
    University of Minnesota, Minnesota, United States
  • Kathy Wabner
    University of Minnesota, Minnesota, United States
  • Jenn Schmit
    University of Minnesota, Minnesota, United States
  • Jana Sellers
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Ju Byung Chae
    Ophthalmology, Chungbuk National University, Chungbuk, Korea (the Republic of)
  • Ravinder Singh
    Mayo Clinic, Minnesota, United States
  • Micah A Chrenek
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Jeffrey H Boatright
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Footnotes
    Commercial Relationships   Timothy Olsen, iMacular Regeneration LLC (I); Timothy Wiedmann, None; Roy Dyer, None; Daniel Paley, None; Kathy Wabner, None; Jenn Schmit, None; Jana Sellers, None; Ju Chae, None; Ravinder Singh, None; Micah Chrenek, None; Jeffrey Boatright, None
  • Footnotes
    Support  Abraham J. & Phyllis Katz Foundation, Unrestricted grant from RPB, Chungbuk National University, JoAnne Smith and Delta Airlines, and Emory University School of Medicine, NIH/NEI department core grant P30 EY006360 (Emory), the Mayo Clinic, Rochester, MN.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3276. doi:
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    • Get Citation

      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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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).

Methods : 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.

Results : 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.

Conclusions : 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.

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