Drug Tissue Distribution of TUDCA From a Biodegradable Suprachoroidal Implant versus Intravitreal or Systemic Delivery in the Pig Model

• Published in: Translational vision science & technology 2020-05, Vol.9 (6), p.11
• Main Authors: Olsen, Timothy W, Dyer, Roy B, Mano, Fukutaro, Boatright, Jeffrey H, Chrenek, Micah A, Paley, Daniel, Wabner, Kathy, Schmit, Jenn, Chae, Ju Byung, Sellers, Jana T, Singh, Ravinder J, Wiedmann, Timothy S
• Format: Article
• Language: English
• Subjects: Animals; Choroid; Intravitreal Injections; Pharmaceutical Preparations; Swine; Taurochenodeoxycholic Acid; Tissue Distribution
• ISSN: 2164-2591; 2164-2591
• DOI: 10.1167/tvst.9.6.11

To determine local ocular tissue levels of the bile acid, tauroursodeoxycholic acid (TUDCA), in the pig model using oral, intravenous (IV), intravitreal injection (IVitI) and low- and high-dose suprachoroidal, sustained-release implants (SCI-L or SCI-H). Forty-six pigs (92 globes) were included in the study. TUDCA was delivered orally in 5 pigs, IV in 4, IVitI in 6, SCI-L in 17, and SCI-H in 14. Testing timeframes varied from the same day (within minutes) for IV; 1 to 6 days, oral; and 1 to 4 weeks, IVitI and SCI. Enucleated globes were dissected, specimens from specific tissues were separated, and TUDCA was extracted and quantified using mass spectrometry. The highest TUDCA tissue levels occurred after IV delivery in the macula (252 ± 238 nM) and peripheral retina (196 ± 171 nM). Macular choroid and peripheral choroid levels were also high (1032 ± 1269 and 1219 ± 1486 nM, respectively). For IVitI delivery, macular levels at day 6 were low (0.5 ± 0.5 nM), whereas peripheral choroid was higher (15.3 ± 16.7 nM). Neither the SCI-L nor SCI-H implants delivered meaningful macular doses (≤1 nM); however, peripheral retina and choroid levels were significantly higher. Bile acid isoforms were found in the serum specimens. The highest TUDCA tissue levels in the pig model were obtained using IV delivery. Oral delivery was associated with reasonable tissue levels. Local delivery (IVitI and SCI) was able to achieve measurable local ocular tissue levels. Diffusional kinetics from the suprachoroidal space follow the choroidal blood flow, away from the macula and toward the periphery.