CLINICAL PHARMACOLOGY

Absorption: The absolute bioavailability of oral ganciclovir under fasting conditions was approximately 5% (n=6) and following food was 6% to 9% (n=32). When ganciclovir was administered orally with food at a total daily dosage of 3 g/day (500 mg q3h, 6 times daily and 1000 mg tid), the steady-state absorption as measured by area under the serum concentration vs time curve (AUC) over 24 hours and maximum serum concentrations (C_max) were similar following both regimens with an AUC_0-24 of 15.9 ± 4.2 (mean ± SD) and 15.4 ± 4.3 µg^.hr/mL and C_max of 1.02 ± 0.24 and 1.18 ± 0.36 µg/mL, respectively (n=16).

At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 µg.hr/mL (n=16) and C_max ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).

Food Effects: When CYTOVENE capsules were given with a meal containing 602 calories and 46.5% fat at a dosage of 1000 mg every 8 hours to 20 HIV-positive subjects, the steady-state AUC increased by 22 ± 22% (range: -6% to 68%) and there was a significant prolongation of time to peak serum concentrations (T_max) from 1.8 ± 0.8 to 3.0 ± 0.6 hours and a higher C_max (0.85 ± 0.25 vs 0.96 ± 0.27 µg/mL) (n=20).

Distribution: The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). For CYTOVENE capsules, no correlation was observed between AUC and reciprocal weight (range: 55 to 128 kg); oral dosing according to weight is not required. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h ranged from 0.31 to 0.68 µg/mL representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Metabolism: Following oral administration of a single 1000 mg dose of ¹⁴C-labeled ganciclovir, 86 ± 3% of the administered dose was recovered in the feces and 5 ± 1% was recovered in the urine (n=4). No metabolite accounted for more than 1% to 2% of the radioactivity recovered in urine or feces.

Elimination: When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was recovered unmetabolized in the urine. Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). After oral administration of ganciclovir, steady-state is achieved within 24 hours. Renal clearance following oral administration was 3.1 ± 1.2 mL/min/kg (n=22). Half-life was 3.5 ± 0.9 hours (n=98) following IV administration and 4.8 ± 0.9 hours (n=39) following oral administration.

Special Populations: Renal Impairment: The pharmacokinetics following intravenous administration of CYTOVENE-IV solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg.

Bookmark this page: