Intravitreal toxicology and therapeutic efficacy of the carboxymethyl ester of the 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a novel lipid antiviral prodrug for intraocular drug delivery

This study was conducted to evaluate the vitreous clarity and intraocular t herapeutic index of three preparations of the carboxymethyl ester of 1-O-oc tadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zeala nd white rabbits were intravitreally injected with one of three preparation s of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intra ocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injectio n of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitre al compound aggregates in eyes with the middle and high doses. The intraocu lar therapeutic index was lower than 465:1. Intravitreal injection of lipos omal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final intravitreal concentrations. No retinal to xicity was confirmed for the 1.12 mM final intravitreal concentration at th e eight week observation following injection. The intraocular therapeutic i ndex was between 585-1037:1. ODG-PFA-O-Me possesses better vitreous compati bility than ODG-PFA. Liposomal ODG-PFA-O-Me can be intravitreally injected with a resulting clear vitreous and high intraocular therapeutic index. Lip osomal ODG-PFA-O-Me could be a long acting nontoxic intravitreous injectabl e drug for CMV retinitis.