Abstract
Purpose :
Endothelin (ET)-1 upregulation is associated with maladaptive vascular remodeling and tissue ischemia present in ocular diseases including glaucoma and diabetic retinopathy (DR). PER-001, a potent and selective endothelin receptor-A (ETA) antagonist, has therapeutic potential to improve retinal perfusion and preserve visual function. A biodegradable PER-001 sustained release implant has been developed that provides first order in vitro drug release for more than 90 days. In this work, the distribution of PER-001 in ocular tissues for up to 12 weeks after administration of PER-001 Implants in Dutch-belted and Rex rabbits was investigated.
Methods :
PER-001 Implants were administered to rabbits as a single bilateral intravitreal injection. Rabbits were sacrificed at predetermined timepoints for pharmacokinetic analysis. The levels of PER-001 in ocular tissues, plasma and residual content in recovered implants were detected by LC-MS/MS analysis.
Results :
In rabbits, the average tissue concentration of PER-001 in various ocular tissues reached the highest levels between 2 and 4 weeks and were measurable until the final timepoints at 10 – 11 weeks post-injection. PER-001 concentrations in the retina and RPE/Choroid remained well over the ETA IC50 of 1.54 nM (0.83 ng/g) throughout the duration of the study, after reaching steady state at 2 weeks. The content of the PER-001 Implants decreased steadily in a linear fashion with complete release between 10 – 12 weeks. Fundus examination revealed no gross morphological abnormalities throughout the study period.
Conclusions :
These results demonstrate that intravitreal administration of PER-001 Implants were well tolerated and has the potential to deliver therapeutic levels of PER-001 to the target ocular tissues (retina and RPE/Choroid) for up to 12 weeks in rabbits.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.