Ganciclovir absolute bioavailability and steady-state pharmacokinetics after oral administration of two 3000-mg/d dosing regimens in human immunodeficiency virus— and cytomegalovirus-seropositive patients

Oral ganciclovir has recently been approved for use in long-term maintenance therapy in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients. Although oral ganciclovir at a dose of 3000 mg/d is moderately less effective than intravenous (IV) ganciclovir maintenance therapy (5 mg/kg as a 1-hour IV infusion every 24 hours), convenience and practicality make oral maintenance therapy desirable. Two dosing regimens—1000 mg three times daily (TID) and 500 mg every 3 hours (six times daily)—have been shown to be efficacious. Eighteen human immunodeficiency virus— and CMV-seropositive patients participated in a three-way, open-label, crossover study to evaluate the steady-state pharmacokinetics and absolute bioavailability of the two oral regimens compared with the IV regimen. Sixteen patients completed the study and received ganciclovir as a single 5-mg/kg IV infusion over 1 hour, 500 mg orally every 3 hours while awake (six times daily) for 3 days, and 1000 mg TID orally for 3 days. Blood samples were obtained over a 24-hour period after the single IV dose and on day 3 of the oral dosing regimens. Mean peak serum concentrations were 8.27, 1.02, and 1.18 μg/mL for the IV and oral regimens, respectively. Twenty-four—hour area under the curve (AUC) for the oral regimens—500 mg every 3 hours and 1000 mg TID—were 15.9 and 15.4 μg • h/mL, respectively, as compared with a total AUC of 22.1 μg • h/mL for the single IV dose. The absolute bioavailabilities for the two oral regimens were 8.84% and 8.53%, respectively. The extent of ganciclovir absorption, peak concentrations, and average concentration at steady state were not statistically different between the two oral regimens. The peak-to-trough concentration ratio (C max:C min) was greater for the 1000-mg TID regimen than for the regimen of 500 mg every 3 hours (5.35 vs 3.81 [ P < 0.01]). Both oral regimens resulted in concentrations in the range of the concentration that inhibits 50% of most human CMV isolates Because both oral regimens provide equivalent absorption, the 1000-mg TID regimen may be preferred for the convenience and potentially greater compliance associated with fewer daily doses.