Abstract
Purpose :
PP-001 is an inhibitor of dihydroorotate dehydrogenase and has a best-in-class pharmacological profile for autoimmune uveitis following oral and intravitreal administration. In Experimental Autoimmune Uveitis PP-001 has shown a profound effect on T cell proliferation and downregulation of IL-17 and IFN-g. This study aimed to evaluate ocular toxicity in vitro and ocular tolerability as well as tissue distribution after topical administration of PP-001 in vivo.
Methods :
In vitro cytotoxicity was measured by quantifying lactate dehydrogenase production in both human conjunctival epithelial (HCjE) and human corneal-limbal epithelial (HCLE) cells incubated with dilutions of PP-001 for 5, 15, and 30 minutes, as well as 24h after 30 minutes of exposure. New Zealand White rabbits (NZW) received instillations of 0.26% PP-001 or vehicle solution (control) 4 times per day over 4 days. 35µl were instilled in both eyes of each animal. Clinical signs and Draize’s scale were evaluated every day. Slit lamp and histopathology examination was performed on day 4. Ocular tissues (cornea, conjunctiva, retina, aqueous humor) and plasma samples were taken on day 1 (single dose) and day 4 and analyzed for PP-001 content with LC/MS.
Results :
PP-001 was well tolerated in in vitro experiments with epithelial cells. Less than 4% and 10% cytotoxicity was determined for HCjE cells and HCLE cells, respectively. Clinical and ocular examination in NZW rabbits did not reveal test article or vehicle related ocular findings in all animals. Histological analysis confirmed that PP-001 was very well tolerated in albino rabbits.
The exposure in tissues after administration of 0.26% PP-001 eye drops was highest in conjunctival tissue with 19283 ng/g, followed by cornea with 12141 ng/g. In plasma, a maximal concentration of 33 ng/ml was found at 0.5 h post dose. No accumulation of PP-001 was detected in plasma and ocular tissues.
Conclusions :
PP-001 is well tolerated in vitro and in vivo when instilled 4 times daily over 4 days. The ocular distribution was highest in conjunctiva and cornea, suggesting a great potential for therapeutic use in inflammatory ocular surface diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.