Abstract
Purpose :
While topical anesthetic agents achieve excellent anesthesia on the external surface of the eye, they do not numb the internal aspect of the pars plana, which is extremely sensitive. Patients often report moderate to severe discomfort during intravitreal injections with currently available analgesics. Articaine is an amide local anesthetic that blocks the generation and conduction of nerve impulses and was selected because of its ability to penetrate soft tissue and bone. Articaine is approved for dental injection. Nonclinical IND-enabling studies were conducted with articaine ophthalmic solution (AG-920) to support clinical development.
Methods :
AG-920 was evaluated in pharmacodynamic, ocular distribution, and ocular toxicity and toxicokinetic studies in rabbit, and articaine was evaluated for melanin binding in vitro. Animals received a single bilateral topical ocular administration of two 35 µL drops of AG-920 with a 30-second dosing interval. Efficacy was assessed by Cochet-Bonnet esthesiometry, plasma and ocular matrices were analyzed with LC-MS/MS methods, and ophthalmic exams, intraocular pressure (IOP), pachymetry, and ocular histopathology were included in the toxicity studies.
Results :
Ocular anesthetic effect was observed for 20 minutes post-dose. Articaine did not significantly bind melanin, and ocular distribution data showed that AG-920 penetrated the globe following topical administration, delivering articaine to the target tissue and rapidly metabolizing to the inactive metabolite. Systemic exposure was minimal, peaked at 15 minutes, and declined quickly. AG-920 was well tolerated in the rabbit, with no tolerability or toxicity findings noted in any ocular or systemic toxicology endpoint. The No Observed Adverse Effect Level was the highest dose administered, 5.6 mg/eye (11.2 mg/animal or 6.6 mg/kg).
Conclusions :
These data demonstrate that AG-920 induces ocular anesthesia, delivers articaine to the target ocular tissues, and was well tolerated in nonclinical studies. The ocular anesthetic activity and safety of AG-920 is currently being evaluated in human subjects (NCT04513652).
This is a 2021 ARVO Annual Meeting abstract.