Dounomycin in the Treatment of Experimental Proliferative Vitreoretinopathy Effective Doses In Vitro and In Vivo Peter Wiedemann,* Nino Sorgente,t Clara Dekhor,j- Randi Patterson,* Tai Tran,* and Stephen J. Ryan" In previous studies the authors have shown that daunomycin, an anthracycline antibiotic, when injected into the vitreous effectively controls experimental proliferative vitreoretinopathy. Here we show that by administering daunomycin intravitreally it is possible to achieve in vivo concentrations that prevent fibroblast proliferation in vitro. The authors have also determined that the half-life of daunomycin in the vitreous is 131 min, indicating that a critical concentration is maintained in the eye for longer than 4 hr after a single injection. Using 3 H-daunomycin, the authors have found that the drug is eliminated across the retina; no significant binding of the drug to vitreous components occurs. These studies demonstrate that it is possible to define the kinetics of drugs injected into the vitreous; and a knowledge of the distribution of any drug in ocular tissues is necessary to effectively determine whether such drug is of therapeutic value. Invest Ophthalmol Vis Sci 26:719-725, 1985 Proliferative vitreoretinopathy (PVR) is the most common complication of retinal reattachment sur- gery. 1 The condition is characterized by the prolifer- ation of cells on both surfaces of the retina, resulting in membrane formation and traction on the retina. 2 If the proliferation of cells in the vitreous that results in re-detachment of the retina could be inhibited, more favorable long-term results of surgery would be obtained. Control of cellular proliferation would pre- vent the secondary processes of contraction and col- lagen deposition, which lead to traction detachment. A drug appropriate for the control of PVR must possess two qualities: it has to inhibit cell proliferation effectively, and it must do this without intolerable toxicity to the retina or other ocular structures. The effectiveness depends on the pharmacodynamic and pharmacokinetic characteristics of the drug. The de- sired pharmacokinetic properties include suitability for local injection into the vitreous, as this results in the highest possible concentration at the target site, thus eliminating or at least reducing systemic toxicity. From the Department of Ophthalmology,* University of Southern California, and the Estelle Doheny Eye Foundation,! Los Angeles, California. Presented in part at the ARVO meeting, May 1983, Sarasota, Florida. Supported in part by grant EY-03040 awarded by the National Institutes of Health (National Eye Institute). Submitted for publication: September 6, 1983. Reprint requests: Stephen J. Rvan. MD, Estelle Doheny Eye Foundation, 1355 San Pablo Street, Los Angeles, CA 90033. The drug must remain in the vitreous long enough to affect the proliferation of cells during a sensitive period of their cycle. Previous studies have shown the anthracycline antibiotic daunomycin to be effective in the control of experimental PVR. A dose response study in the rabbit showed that the detachment score, which is a measure of the severity of membrane formation and traction detachment following intravitreal injection of cultured fibroblasts, was significantly lower in treated animals than in controls. At high doses, however, there was marked toxicity to the retina, causing detachment and degeneration. 3 Obviously, it is very important to determine whether it is possible to achieve useful concentrations of the drug at the target site and whether such concentrations last long enough to be of value in treating clinical PVR. To determine what minimal dose has to be maintained for what length of time in the vitreous to prevent proliferation of fibroblasts without toxicity to the retina, we determined cell survival into vitro after exposure to daunomycin and performed pharmacokinetic studies in the rabbit to determine the concentrations of daunomycin and its metabolite daunomycinol in the vitreous and other ocular tissues. Materials and Methods Materials Amphotericin B was purchased from Sauibb (Princeton, NJ); Ciaramycin, from Schering Corpo- 719