CLINICAL PHARMACOLOGY
: Pharmacokinetics:
BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR
IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE
ARE REQUIRED FOR CYTOVENE-IV AND SHOULD BE CONSIDERED
FOR CYTOVENE CAPSULES. FOR DOSING INSTRUCTIONS IN PATIENTS
WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.
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 (Cmax)
were similar following both regimens with an AUC0-24
of 15.9 ± 4.2 (mean ± SD) and 15.4 ± 4.3 µg.hr/mL
and Cmax 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 Cmax 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 (Tmax) from 1.8
± 0.8 to 3.0 ± 0.6 hours and a higher Cmax (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.
Estimated
Creatinine Clearance
(mL/min) |
n |
Dose |
Clearance
(mL/min)
Mean ± SD |
Half-life
(hours)
Mean ± SD |
50-79
25-49
<25 |
4
3
3 |
3.2-5 mg/kg
3-5 mg/kg
1.25-5 mg/kg |
128 ± 63
57 ± 8
30 ± 13 |
4.6 ± 1.4
4.4 ± 0.4
10.7 ± 5.7 |
The pharmacokinetics of ganciclovir following oral administration
of CYTOVENE capsules were evaluated in 44 patients, who
were either solid organ transplant recipients or HIV positive.
Apparent oral clearance of ganciclovir decreased and AUC0-24h
increased with diminishing renal function (as expressed
by creatinine clearance). Based on these observations,
it is necessary to modify the dosage of ganciclovir in
patients with renal impairment (see DOSAGE AND ADMINISTRATION).
Hemodialysis reduces plasma concentrations of ganciclovir
by about 50% after both intravenous and oral administration.
Race/Ethnicity and Gender: The effects of race/ethnicity
and gender were studied in subjects receiving a dose regimen
of 1000 mg every 8 hours. Although the numbers of blacks
(16%) and Hispanics (20%) were small, there appeared to
be a trend towards a lower steady-state Cmax
and AUC0-8 in these subpopulations as compared
to Caucasians. No definitive conclusions regarding gender
differences could be made because of the small number
of females (12%); however, no differences between males
and females were observed.
Pediatrics: Ganciclovir pharmacokinetics were
studied in 27 neonates, aged 2 to 49 days. At an intravenous
dose of 4 mg/kg (n=14) or 6 mg/kg (n=13), the pharmacokinetic
parameters were, respectively, Cmax of 5.5
± 1.6 and 7.0 ± 1.6 µg/mL, systemic clearance of 3.14
± 1.75 and 3.56 ± 1.27 mL/min/kg, and t1/2
of 2.4 hours (harmonic mean) for both.
Ganciclovir pharmacokinetics were also studied in 10
pediatric patients, aged 9 months to 12 years. The pharmacokinetic
characteristics of ganciclovir were the same after single
and multiple (q12h) intravenous doses (5 mg/kg). The steady-state
volume of distribution was 0.64 ± 0.22 L/kg, Cmax
was 7.9 ± 3.9 µg/mL, systemic clearance was 4.7 ± 2.2
mL/min/kg, and t1/2 was 2.4 ± 0.7 hours. The
pharmacokinetics of intravenous ganciclovir in pediatric
patients are similar to those observed in adults.
Elderly: No studies have been conducted in adults
older than 65 years of age. |
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