Bioavailability of Ganciclovir from a Sustained-release Ganciclovir Intraocular Implant in Silicone Oil: An In Vitro Study

Abstract

Abstract: : Purpose: The sustained-release ganciclovir intraocular implant has been shown to be effective in the treatment of cytomegalovirus (CMV) retinitis. In cases with retinal detachment, the use of silicone oil to provide post-vitrectomy retinal tamponade has been shown to be effective in improving retinal reattachment. It is not known if the ganciclovir implant when used in combination with silicone oil will release ganciclovir into silicone oil so that it is bioavailable to the retina. Methods: Three sustained-release ganciclovir implants were submerged in individual spherical-bottomed glass flasks (5 ml) containing 4 ml silicone oil. To determine diffusion favoring a concentration gradient, three additional flasks containing 1 ml highly concentrated (~150 mg/ml) aqueous solution of ganciclovir were layered with 3 ml silicone oil, providing a concentration gradient of 0:150,000 ppm. All flasks were kept at a constant temperature of 37^o C. Samples were drawn at 1, 2, 4, 8, 16, 32, 64, and 140 days. Aliquots (100 µg) of silicone oil from the surface of each flask were diluted with ethyl acetate:ethanol (9:1, v/v) and extracted with distilled water. Ganciclovir was quantitated by analyzing extracted samples using high performance liquid chromatography (HPLC). Three implants were submerged in aqueous solution (as described) and used to determine the normal ganciclovir release rate from the implants. Results: No ganciclovir was detected in silicone oil from any of the six flasks containing either a ganciclovir implant submerged in silicone oil or in direct contact with high concentration aqueous solution of ganciclovir, providing a large surface area for diffusion. The release rate of ganciclovir from implants in aqueous solution was shown to be within the range reported in previous studies. Conclusions: Ganciclovir implants, when submerged in silicone oil, did not significantly release ganciclovir. Ganciclovir could not partition from a highly concentrated aqueous layer into silicone oil when it remained in contact for months. Ganciclovir implants and intraocular ganciclovir injections, when used in combination with silicone oil in the treatment of CMV retinitis, cannot provide penetration of ganciclovir into silicone oil in contact with retina.

Keywords: cytomegalovirus • pharmacology • retinitis