CLINICAL PHARMACOLOGY
MICROBIOLOGY
Mechanism of Antiviral Activity
Famciclovir undergoes rapid biotransformation to the
active antiviral compound penciclovir, which has inhibitory
activity against herpes simplex virus types 1 (HSV-1)
and 2 (HSV-2) and varicella zoster virus (VZV). In cells
infected with HSV-1, HSV-2 or VZV, viral thymidine kinase
phosphorylates penciclovir to a monophosphate form that,
in turn, is converted to penciclovir triphosphate by cellular
kinases. In vitro studies demonstrate that penciclovir
triphosphate inhibits HSV-2 DNA polymerase competitively
with deoxyguanosine triphosphate. Consequently, herpes
viral DNA synthesis and, therefore, replication are selectively
inhibited.
Penciclovir triphosphate has an intracellular half-life
of 10 hours in HSV-1-,20 hours in HSV-2- and 7 hours in
VZV-infected cells cultured in vitro; however, the clinical
significance is unknown.
Antiviral Activity In Vitro and In Vivo
In cell culture studies, penciclovir has antiviral activity
against the following herpes viruses (listed in decreasing
order of potency): HSV-1, HSV-2 and VZV. Sensitivity test
results, expressed as the concentration of the drug required
to inhibit the growth of the virus by 50% (IC50) or 99%
(IC99) in cell culture, vary greatly depending upon a
number of factors, including the assay protocols, and
in particular the cell type used.See Table 1.
Table 1
| Method
of Assay |
Virus
Type |
Cell
Type |
IC50(mcg/mL) |
IC99 |
| Plaque Reduction |
VZV (c.i.) |
MRC-5 |
5.0 ± 3.0 |
|
| |
VZV (c.i.) |
Hs68 |
0.9 ± 0.4 |
|
| |
HSV-1 (c.i.) |
MRC-5 |
0.2 0.6 |
|
| |
HSV-1 (c.i.) |
WISH |
0.04
0.5 |
|
| |
HSV-2 (c.i.) |
MRC-5 |
0.9 2.1 |
|
| |
HSV-2 (c.i.) |
WISH |
0.1 0.8 |
|
| Virus Yield |
HSV-1 (c.i.) |
MRC-5 |
|
0.4 0.5 |
| Reduction |
HSV-2 (c.i.) |
MRC-5 |
|
0.6 0.7 |
| DNA Synthesis |
VZV (Ellen) |
MRC-5 |
0.1 |
|
| Inhibition |
HSV-1 (SC16) |
MRC-5 |
0.04 |
|
| |
HSV-2 (MS) |
MRC-5 |
0.05 |
|
(c.i) = clinical isolates.
Drug Resistance
Penciclovir-resistant mutants of HSV and VZV can result
from complete loss of viral thymidine kinase activity
(TK negative), reduced TK activity (TK altered) or DNA
polymerase mutations. The most commonly encountered acyclovir-resistant
mutants that are TK negative are also resistant to penciclovir.
The possibility of viral resistance to penciclovir should
be considered in patients who fail to respond or experience
recurrent viral infections during therapy.
PHARMACOKINETICS
Absorption and Bioavailability
Famciclovir is the diacetyl 6-deoxy analog of the active
antiviral compound penciclovir. Following oral administration,
little or no famciclovir is detected in plasma or urine.
The absolute bioavailability of famciclovir is 77±8%
as determined following the administration of a 500 mg
famciclovir oral dose and a 400 mg penciclovir intravenous
dose to 12 healthy male subjects.
Penciclovir concentrations increased in proportion to
dose over a famciclovir dose range of 125 mg to 750 mg
administered as a single dose. Single oral dose administration
of 125 mg, 250 mg or 500 mg famciclovir to healthy male
volunteers across 17 studies gave the following pharmacokinetic
parameters:
Table 2
| Dose |
AUC (0-¥)
(mcghr./mL) |
Cmax
(mcg/mL) |
Tmax
§ (h) |
| 125 mg |
2.24 |
0.8 |
0.9 |
| 250 mg |
4.48 |
1.6 |
0.9 |
| 500 mg |
8.95 |
3.3 |
0.9 |
†AUC (0-¥)(mcg•hr./mL)=area under the plasma
concentration-time profile extrapolated to infinity.
‡Cmax (mcg/mL)=maximum observed plasma concentration.
§Tmax (h)= time to Cmax.
Following single oral-dose administration of 500 mg famciclovir
to seven patients with herpes zoster, the mean ±SD
AUC, Cmax ,and Tmax were 12.1±1.7 mcg•hr./mL,
4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively.
The AUC of penciclovir was approximately 35% greater in
patients with herpes zoster as compared to healthy volunteers.
Some of this difference may be due to differences in renal
function between the two groups.
There is no accumulation of penciclovir after the administration
of 500 mg famciclovir t.i.d. for 7 days.
Penciclovir Cmax decreased approximately 50% and Tmax
was delayed by 1.5 hours when a capsule formulation of
famciclovir was administered with food (nutritional content
was approximately 910 Kcal and 26% fat). There was no
effect on the extent of availability (AUC) of penciclovir.
There was an 18% decrease in Cmax and a delay in Tmax
of about 1 hour when famciclovir was given 2 hours after
a meal as compared to its administration 2 hours before
a meal. Because there was no effect on the extent of systemic
availability of penciclovir, it appears that Famvir can
be taken without regard to meals.
Distribution
The volume of distribution (Vdb) was 1.08±0.171/kg
in 12 healthy male subjects following a single intravenous
dose of penciclovir at 400 mg administered as a 1-hour
intravenous infusion.
Penciclovir is <20% bound to plasma proteins over
the concentration range of 0.1 to 20 mcg/mL. The blood/plasma
ratio of penciclovir is approximately 1.
Metabolism
Following oral administration, famciclovir is deacetylated
and oxidized to form penciclovir. Metabolites that are
inactive include 6-deoxy penciclovir, monoacetylated penciclovir,
and 6-deoxy monoacetylated penciclovir (5%, <0.5% and
<0.5% of the dose in the urine, respectively). Little
or no famciclovir is detected in plasma or urine.
An in vitro study using human liver microsomes demonstrated
that cytochrome P450 does not play an important role in
famciclovir metabolism. The conversion of 6-deoxy penciclovir
to penciclovir is catalyzed by aldehyde oxidase.
Elimination
Approximately 94% of administered radioactivity was recovered
in urine over 24 hours (83% of the dose was excreted in
the first 6 hours) after the administration of 5 mg/kg
radiolabeled penciclovir as a 1-hour infusion to three
healthy male volunteers. Penciclovir accounted for 91%
of the radioactivity excreted in the urine.
Following the oral administration of a single 500 mg
dose of radiolabeled famciclovir to three healthy male
volunteers, 73% and 27% of administered radioactivity
were recovered in urine and feces over 72 hours, respectively.
Penciclovir accounted for 82% and 6-deoxy penciclovir
accounted for 7% of the radioactivity excreted in the
urine. Approximately 60% of the administered radiolabeled
dose was collected in urine in the first 6 hours.
After intravenous administration of penciclovir in 48
healthy male volunteers, mean ±S.D. total plasma
clearance of penciclovir was 36.6±6.3 L/hr (0.48±0.09
L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8%
of total plasma clearance.
Renal clearance of penciclovir following the oral administration
of a single 500 mg dose of famciclovir to 109 healthy
male volunteers was 27.7±7.6 L/hr. The plasma elimination
half-life of penciclovir was 2.0±0.3 hours after
intravenous administration of penciclovir to 48 healthy
male volunteers and 2.3±0.4 hours after oral administration
of 500 mg famciclovir to 124 healthy male volunteers.
The half-life in seven patients with herpes zoster was
3.0±1.1 hours.
HIV-lnfected Patients
Following oral administration of a single dose of 500
mg famciclovir (the oral prodrug of penciclovir) to HIV-positive
patients, the pharmacokinetic parameters of penciclovir
were comparable to those observed in healthy subjects.
Renal Insufficiency
Apparent plasma clearance, renal clearance, and the plasma-elimination
rate constant of penciclovir decreased linearly with reductions
in renal function. After the administration of a single
500 mg famciclovir oral dose (n=27) to healthy volunteers
and to volunteers with varying degrees of renal insufficiency
(CLCR ranged from 6.4 to 138.8 mL/min.), the following
results were obtained (Table 3):
Table 3
| Parameter
(mean±S.D.) |
CLCR
60(mL/min.) |
CLCR
40-59(mL/min.) |
CLCR
20-39(mL/min.) |
CLCR
<20(mL/min.) |
| CLCR
(mL/min) |
88.1±20.6 |
49.3±5.9 |
26.5±5.3 |
12.7±5.9 |
|
CLR (L/hr) |
30.1±10.6 |
13.0±1.3 |
4.2±0.9 |
1.6±1.0 |
|
CL/F§ (L/hr) |
66.9±27.5 |
27.3±2.8 |
12.8±1.3 |
5.8±
2.8 |
|
Half-life (hr) |
2.3±0.5 |
3.4±0.7 |
6.2±1.6 |
13.4±10.2 |
| n |
15 |
5 |
4 |
3 |
†CLCR is measured creatinine clearance.
‡n=4.
§ CL/F consists of bioavailability factor and famciclovir
to penciclovir conversion factor.
In a multiple dose study of famciclovir conducted in
subjects with varying degrees of renal impairment (n=18),
the pharmacokinetics of penciclovir were comparable to
those after single doses.
A dosage adjustment is recommended for patients with
renal insufficiency (see DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
Well-compensated chronic liver disease (chronic hepatitis
[n=6], chronic ethanol abuse [n=8], or primary biliary
cirrhosis [n=1]) had no effect on the extent of availability
(AUC) of penciclovir following a single dose of 500 mg
famciclovir. However, there was a 44% decrease in penciclovir
mean maximum plasma concentration and the time to maximum
plasma concentration was increased by 0.75 hours in patients
with hepatic insufficiency compared to normal volunteers.
No dosage adjustment is recommended for patients with
well-compensated hepatic impairment. The pharmacokinetics
of penciclovir have not been evaluated in patients with
severe uncompensated hepatic impairment.
Elderly Subjects
Based on cross-study comparisons, mean penciclovir AUC
was 40% larger and penciclovir renal clearance was 22%
lower after the oral administration of famciclovir in
elderly volunteers (n=18, age 65 to 79 years) compared
to younger volunteers. Some of this difference may be
due to differences in renal function between the two groups.
Gender
The pharmacokinetics of penciclovir were evaluated in
18 healthy male and 18 healthy female volunteers after
single-dose oral administration of 500 mg famciclovir.
AUC of penciclovir was 9.3±1.9 mcg•hr./mL
and 11.1±2.1 mcg•hr./mL in males and females,
respectively. Penciclovir renal clearance was 28.5±8.9
L/hr and 21.8±4.3 L/hr, respectively. These differences
were attributed to differences in renal function between
the two groups. No famciclovir dosage adjustment based
on gender is recommended.
Pediatric Patients
The pharmacokinetics of famciclovir or penciclovir have
not been evaluated in patients <18 years of age.
Race
The pharmacokinetics of famciclovir or penciclovir with
respect to race have not been evaluated.
Drug Interactions
Effects on penciclovir
No clinically significant alterations in penciclovir
pharmacokinetics were observed following single-dose administration
of 500 mg famciclovir after pre-treatment with multiple
doses of allopurinol, cimetidine, theophylline, or zidovudine.
No clinically significant effect on penciclovir pharmacokinetics
was observed following multiple-dose (t.i.d.) administration
of famciclovir (500 mg) with multiple doses of digoxin.
Effects of famciclovir on co-administered drugs
The steady-state pharmacokinetics of digoxin were not
altered by concomitant administration of multiple doses
of famciclovir (500 mg t.i.d.). No clinically significant
effect on the pharmacokinetics of zidovudine or zidovudine
glucuronide was observed following a single oral dose
of 500 mg famciclovir.
CLINICAL TRIALS
Herpes Zoster
Famvir (famciclovir) was studied in a placebo-controlled,
double-blind trial of 419 immunocompetent adults with
uncomplicated herpes zoster. Comparisons included Famvir
500 mg t.i.d., Famvir 750 mg t.i.d., or placebo. Treatment
was begun within 72 hours of initial lesion appearance
and therapy was continued for 7 days.
The median time to full crusting in Famvir-treated patients
was 5 days compared to 7 days in placebo-treated patients.
The times to full crusting, loss of vesicles, loss of
ulcers, and loss of crusts were shorter for Famvir 500
mg treated patients than for placebo-treated patients
in the overall study population. The effects of Famvir
were greater when therapy was initiated within 48 hours
of rash onset; it was also more pronounced in patients
50 years of age or older. Among the 65.2% of patients
with at least one positive viral culture, Famvir-treated
patients had a shorter median duration of viral shedding
than placebo-treated patients (1 day and 2 days, respectively).
There were no overall differences in the duration of
pain before rash healing between Famvir and placebo-treated
groups. In addition, there was no difference in the incidence
of pain after rash healing (postherpetic neuralgia) between
the treatment groups. In the 186 patients (44.4% of total
study population) who did develop postherpetic neuralgia,
the median duration of postherpetic neuralgia was shorter
in patients treated with Famvir 500 mg than in those treated
with placebo (63 days and 119 days, respectively). No
additional efficacy was demonstrated with higher doses
of Famvir.
A double-blind controlled trial in 545 immunocompetent
adults with uncomplicated herpes zoster treated within
72 hours of initial lesion appearance compared three doses
of Famvir to acyclovir 800 mg 5 times per day. Times to
full lesion crusting and times to loss of acute pain were
comparable for all groups and there were no statistically
significant differences in the time to loss of postherpetic
neuralgia between Famvir and acyclovir-treated groups.
Herpes Simplex Infections
Recurrent Genital Herpes
In two placebo-controlled trials, 626 immunocompetent
adults with a recurrence of genital herpes were treated
with Famvir 125 mg b.i.d.(n=160), Famvir 250 mg b.i.d.(n=169),
Famvir 500 mg b.i.d.(n=154) or placebo (n=143) for 5 days.
Treatment was initiated within 6 hours of either symptom
onset or lesion appearance. In the two studies combined,
the median time to healing in Famvir 125 mg-treated patients
was 4 days compared to 5 days in placebo-treated patients
and the median time to cessation of viral shedding was
1.8 vs. 3.4 days in Famvir 125 mg and placebo recipients,
respectively. The median time to loss of all symptoms
was 3.2 days in Famvir 125 mg-treated patients vs. 3.8
days in placebo-treated patients. No additional efficacy
was demonstrated with higher doses of Famvir.
Suppression of Recurrent Genital Herpes
934 immunocompetent adults with a history of 6 or more
recurrences per year were randomized into two double-blind,
1-year, placebo-controlled trials. Comparisons included
Famvir 125 mg t.i.d., 250 mg b.i.d., 250 mg t.i.d. and
placebo. At one-year, 60% to 65% of patients were still
receiving Famvir and 25% were receiving placebo treatment.
Patient reported recurrence rates for the 250 mg b.i.d.
dose at 6 and 12 months are shown in Table 4.
Table 4
| |
Recurrence Rates
at 6 Months
|
Recurrence Rates
at 12 Months
|
| |
Famvir
250 mg
b.i.d. |
Placebo |
Famvir
250 mg
b.i.d. |
Placebo |
| n |
236 |
233 |
236 |
233 |
| Recurrence-free |
39% |
10% |
29% |
6% |
| Recurrences |
47% |
74% |
53% |
78% |
| Lotto Follow-up |
14% |
16% |
17% |
16% |
† Based on patient reported data; not necessarily
confirmed by a physician.
‡ Patients recurrence-free at time of last contact
prior to withdrawal.
Famvir-treated patients had approximately 1/5 the median
number of recurrences as compared to placebo-treated patients.
Higher doses of Famvir were not associated with an increase
in efficacy.
Recurrent Mucocutaneous Herpes Simplex Infection
in HIV-lnfected Patients
A randomized, double-blind, multicenter study compared famciclovir
500 mg twice daily for 7 days (n=150) with oral acyclovir
400 mg 5 times daily for 7 days (n=143) in HIV-infected
patients with recurrent mucocutaneous HSV infection treated
within 48 hours of lesion onset. Approximately 40% of patients
had a CD4 count below 200 cells/mm3 ,54% of patients had
anogenital lesions and 35% had orolabial lesions. Famciclovir
therapy was comparable to oral acyclovir in reducing new
lesion formation and in time to complete healing.
| |
