Abstract
Purpose :
CLS011A is a small molecule with anti-VEGFr and anti-PDGFr binding properties. The purpose of this study was to assess the pharmacokinetics and ocular tissue distribution following a single bilateral suprachoroidal injection of 4 mg CLS011A to each eye of pigmented Dutch Belted rabbits.
Methods :
On Day 0, 14 male rabbits were administered a single bilateral suprachoroidal injection of CLS011A. Ophthalmic exams occurred pre-dose and on Study Days 4, 15, 28, and 91 prior to sacrifice, as applicable. On specified days through Study Day 91, two animals/time point were euthanized for the collection of blood for plasma and ocular tissues: aqueous humor, vitreous humor, retina, and sclera/choroid-RPE. Plasma and ocular tissues were analyzed for concentrations of CLS011A by the Covance-Madison Discovery Bioanalytical Department using LC-MS/MS.
Results :
Suprachoroidal administration of CLS011A at 4 mg/eye (100 mL/injection) was well tolerated through Study Day 91. No overt signs of toxicity were observed. CLS011A was not detected at quantifiable levels in either plasma or aqueous humor samples. CLS011A was quantifiable at all time points in the vitreous humor, retina, and sclera/choroid-RPE (SCR). A concentration gradient of CLS011A in tissues was present, with the SCR being highest, followed by the retina, and finally the vitreous humor with the lowest concentrations. The elimination half-life was calculated to be 102 days and more than 60% of CLS011A remained in the SCR at 3 months post injection.
Conclusions :
A single bilateral suprachoroidal administration of 4 mg/eye CLS011A was well tolerated in the pigmented Dutch Belted rabbit. Systemic exposure to CLS011A was minimal, and absorption of CLS011A into the posterior segment of the eye was observed with minimal CLS011A exposure to the anterior segment of the eye. The calculated half-life in the SCR is greater than 3 months and the retina levels are greater than 1 million fold above the IC50 of CLS011A for VEGFr and PDGFr. These data suggest that suprachoroidal drug injection results in distribution and duration of CLS011A that could be beneficial for an agent with an extended duration for the potential treatment of a retinal disease such as neovascular age-related macular degeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.