Absolute bioavailability and dose proportionality of oral ganciclovir after ascending multiple doses in human immunodeficiency virus (HIV)-positive patients

This study was designed to determine the bioavailability and dose linearity and proportionality of ganciclovir after multiple oral administrations of 3,000 mg to 6,000 mg per day. In an open-label, randomized, four-treatment crossover design, 24 patients seropositive for human immunodeficiency virus (HN) and cytomegalovirus (CMV) received in random order multiple oral dose s of ganciclovir 1,000 mg every 3 hours (six times a day), 1,000 mg four li mes a day, and 1,000 mg three times a day and a single 5-mg/kg intravenous infusion (over I hour) of ganciclovir. Blood samples for pharmacokinetic de terminations were obtained on day 3 of each oral regimen and on the day of the intravenous infusion over a 24-hour time interval. Mean steady-state av erage serum concentrations of ganciclovir rr ere 0.54, 0.79, and 0.99 mu g/ mL, respectively, with the 3, 4, and 6 g/day or al regimens. The steady-sta te area under the concentration-time curve (AUC(0-24)) for the 6,000 mg/day oral regimen approached that of the single-dose intravenous regimen. There rr as a proportional increase in AUC(0-24) between the 3 and 4 g/day dosag e regimens, but not between the 4 and 6 g/day regimens. This suggests nonli near absorption of ganciclovir at higher dosages, although the departure fr om proportionality was less than 11%. (C) 1998 The American College of Clin ical Pharmacology.