An Animal Model for Cidofovir (HPMPC) Toxicity: Intraocular Pressure and Histopathologic Effects

Abstract Intravitreal cidofovir has been shown to be a long acting and highly efficacious treatment for CMV retinitis; however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concentrations of 25, 200, 625 and 2000 μg ml −1 . Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 μg ml −1 . A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 μg of cidofovir intravitreally (vitreous concentration of 25 μg ml −1 ) is the highest non-toxic dose in the guinea pig; the IOP was unchanged at two and four weeks after injection with this dose; histologically the eyes were normal. A single injection of 50 μg of cidofovir intravitreally (vitreous concentration of 200 μg ml −1 ) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 μg and 500 μg of cidofovir (vitreous concentrations of 625, and 2000 μg ml −1 , respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 μg cidofovir intravitreally (vitreous concentration of 625 μg ml −1 ); retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 μg of cidofovir intravitreally (vitreous concentration of 2000 μg  ml −1 ); retina was relatively well preserved. The guinea pig eye shows similar reduction in IOP and ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. However, the reduction of IOP caused by cidofovir occurs in the guinea pig eye at a concentration 40 times higher than was observed in the human eye.