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 (HIV) and cytomegalovirus (CMV) received in random order multiple oral doses of ganciclovir 1,000 mg every 3 hours (six times a day), 1,000 mg four times a day, and 1,000 mg three times a day and a single 5-mg/kg intravenous infusion (over 1 hour) of ganciclovir. Blood samples for pharmacokinetic determinations 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 average serum concentrations of ganciclovir were 0.54, 0.79, and 0.99 microgram/mL, respectively, with the 3, 4, and 6 g/day oral regimens. The steady-state area under the concentration-time curve (AUC0-24) for the 6,000 mg/day oral regimen approached that of the single-dose intravenous regimen. There was a proportional increase in AUC0-24 between the 3 and 4 g/day dosage regimens, but not between the 4 and 6 g/day regimens. This suggests nonlinear absorption of ganciclovir at higher dosages, although the departure from proportionality was less than 11%.