Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.
OBJECTIVE
To determine intraocular toxicity and efficacy of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long-acting, nontoxic intravitreous injectable drug delivery system for cytomegalovirus (CMV) retinitis.


METHODS
ODG-PFA was synthesized by coupling the phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and formulated as micelles and liposomes at concentrations so that, after injection into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM, 0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63 mM for liposomal formulation. The compounds were injected, and toxicology evaluations were performed.


RESULTS
Intravitreal injections of micellar ODG-PFA resulted in aggregation of the material in vitreous and variable local retinal damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion of the compounds and a clear vitreous, using final concentration in the vitreous of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was 0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal injection was estimated to be 1470:1.


CONCLUSIONS
Lipid-derivatized foscarnet liposome formulations may be a useful long-acting delivery system for the therapy of CMV retinitis.
Cheng
L
L
Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
Hostetler
K Y
KY
Gardner
M F
MF
Avila
C P
CP
Bergeron-Lynn
G
G
Keefe
K S
KS
Wiley
C A
CA
Freeman
W R
WR
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000633:toxicity*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004596:Electroretinography / Q000187:drug effects; D005451:Fluorescein Angiography; D017245:Foscarnet / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D007267:Injections; D008081:Liposomes; D008826:Microbial Sensitivity Tests; D010742:Phospholipid Ethers / Q000138:chemical synthesis / Q000633:toxicity*; D010857:Pigment Epithelium of Eye / Q000187:drug effects / Q000648:ultrastructure; D011355:Prodrugs / Q000138:chemical synthesis / Q000633:toxicity*; D011817:Rabbits; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D014822:Vitreous Body / Q000187:drug effects
C119381:1-O-octadecyl-sn-glycerol-3-phosphonoformate; D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D010742:Phospholipid Ethers; D011355:Prodrugs; D017245:Foscarnet