Intraocular properties of hexadecyloxypropyl-cyclic-cidofovir in Guinea pigs.

Objective: We previously reported a long-lasting crystalline lipid pro-drug of cyclic cidofovir, hexadecyloxypropyl-cyclic-cidofovir (HDP-cCDV), to treat experimental retinitis in rabbit eyes. With HDP-cCDV there was a longer intraocular therapeutic effect than with cidofovir (CDV) and no toxicity with 100 microg/eye. It has been known that CDV and related analogues lower intraocular pressure (IOP) after local use, and it is also accepted that the guinea pig is a better model to study this toxicity before human clinical trials.

Methods: HDP-cCDV was intravitreally injected into 10 guinea pig eyes in doses of 4, 9, and 18 microg in 20 microL/eye. An 18-microg quantity is the dose equivalent to 100 microg/eye in the rabbit. Only one eye of each animal received drug and the fellow eye served as the control. After injection, the eyes were monitored with tonometry, ophthalmoscopy, electroretinography (ERG), and histology.

Results: Intravitreal injections of doses of 18 microg/eye or lower revealed no toxicity and a high therapeutic index (132,000 to 3300 times higher than the 50% effective concentration for human cytomegalovirus) during 10 weeks of observation. The crystalline drug depot was ophthalmoscopically visible in the inferior vitreous cavity for 5-10 weeks. There was no difference in IOP between the drug-injected and control eyes at any time points (P > 0.05) except for day 3 after drug injection (P = 0.0338). All eyes demonstrated a normal ERG waveform with no differences between the treated and the fellow control eyes (P = 0.85). Histology revealed normal morphology and structures of the retina and ciliary body in all eyes (with or without treatment).

Conclusion: Crystalline HDP-cCDV may be a long-lasting and safer alternative to cidofovir to treat CMV retinitis without the retinal or ciliary body toxicity observed with CDV.