Intravitreal pharmacokinetics in rabbits of the foscarnet lipid prodrug:: 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA)

Purpose. To evaluate the intraocular distribution and metabolism of the lipid pro drug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA), following intravitreal administration. Methods. Twenty rabbits received ODG-[C-14]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal concentration. Two animals per group were sacrificed at different intervals post-injection. The drug levels in ocular tissues were determined with counting the radioactivity by Tracer Mark III Liquid Scintillation Counter. Four rabbits were used for analysis of the drug metabolism in vitreous by lipid extraction technique. Results. The drug level in vitreous was 526 mu M at day one and 227 mu M at the fifth week. The vitreous half life was approximately four to five weeks. The retinal level of the drug was 292 mu M at day one, 75 mu M at the fifth week and 32 mu M at the tenth week, which was still more than ten times higher than the IC90 against HCMV. Lipid extraction analysis showed that, in vivo, both ODG-PFA and PFA were present in vitreous, but in in vitro incubations with vitreous, ODG-PFA conversion to PFA was negligible. Conclusion. ODG-PFA possesses a long vitreous half life and sustained high drug level in retina. The vitreous did not metabolize drug but acted as a drug reservoir. Intravitreal liposomal ODG-PFA may be expected to be a long acting potent local therapy for CMV retinitis.