As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.