A Pharmacodynamic Model of Ganciclovir Antiviral Effect and Toxicity for Lymphoblastoid Cells Suggests a New Dosing Regimen To Treat Cytomegalovirus Infection

Abstract

ABSTRACT In bone marrow transplantation, the efficacy of ganciclovir in cytomegalovirus (CMV) disease treatment or prophylaxis remains partial. Because its hematological toxicity is dose limiting, optimization of the dosing schedule is required to increase its therapeutic index. The goal of our study was to describe the influence of the ganciclovir concentration and duration of exposure on cell survival and antiviral efficacy. The study was carried out in vitro on cultures of lymphoblastoid cells infected or not with the CMV AD169 reference strain and exposed to ganciclovir at different concentrations for 1, 2, 7, or 14 days. The data were analyzed by a mathematical model that allowed a quantitative characterization of ganciclovir pharmacodynamics and its variability. Simulations of the model were undertaken to determine the optimal concentration profile for maximizing the ganciclovir therapeutic index. Ganciclovir had very little toxic and antiviral effect, even at 20 mg liter −1 , when the duration of exposure was ≤7 days. A biologically significant effect was observed only with a 14-day exposure. Complete inhibition of viral replication was obtained at 20 mg liter −1 . The utility function, assuming equal weights for antiviral effect and toxicity, showed that maximal utility was reached around 10 mg liter −1 . The optimal ganciclovir concentration profile consisted of maintaining the concentration at 20 mg liter −1 at the intervals 0 to 2 days and 7.58 to 9.58 days and a null concentration at other times. This optimal profile could be obtained by intravenous (i.v.) ganciclovir at 10 mg/kg of body weight twice daily (b.i.d.) at days 1, 2, 8.5, and 9.5 in stem cell transplant patients with normal renal function.