A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Valtrex Pharmacology, Pharmacokinetics, Studies, Metabolism - Valacyclovir hydrochloride
Valtrex Pharmacology, Pharmacokinetics, Studies, Metabolism - Valacyclovir hydrochloride
CLINICAL PHARMACOLOGY
After oral administration, valacyclovir hydrochloride is rapidly
absorbed from the gastrointestinal tract and nearly completely converted to
acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
Pharmacokinetics
The pharmacokinetics of valacyclovir and acyclovir
after oral administration of VALTREX have been investigated in 14 volunteer
studies involving 283 adults.
Absorption and Bioavailability
The absolute bioavailability of acyclovir after administration
of VALTREX is 54.5% ± 9.1% as determined following a 1-gram oral dose of VALTREX
and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir
bioavailability from the administration of VALTREX is not altered by administration
with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of
fat).
There was a lack of dose proportionality in acyclovir maximum
concentration (Cmax) and area under the acyclovir concentration-time
curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750
mg, and 1 gram of VALTREX to 8 healthy volunteers. The mean Cmax (±
SD) was 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65
(± 2.37) mcg/mL, respectively; and the mean AUC (± SD) was 2.28 (± 0.40), 5.76
(± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr•mcg/mL, respectively.
There was also a lack of dose proportionality in acyclovir
Cmax and AUC after the multiple-dose administration of 250 mg, 500
mg, and 1 gram of VALTREX administered 4 times daily for 11 days in parallel
groups of 8 healthy volunteers. The mean Cmax (± SD) was 2.11 (±
0.33), 3.69 (± 0.87), and 4.96 (± 0.64) mcg/mL, respectively, and the mean AUC
(± SD) was 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr•mcg/mL, respectively.
There is no accumulation of acyclovir after the administration
of valacyclovir at the recommended dosage regimens in healthy volunteers with
normal renal function.
Distribution
The binding of valacyclovir to human plasma proteins ranged
from 13.5% to 17.9%.
Metabolism
After oral administration, valacyclovir hydrochloride is rapidly
absorbed from the gastrointestinal tract. Valacyclovir is converted to acyclovir
and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is
converted to a small extent to inactive metabolites by aldehyde oxidase and
by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is
metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted
valacyclovir are low and transient, generally becoming non-quantifiable by 3
hours after administration. Peak plasma valacyclovir concentrations are generally
less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram
of VALTREX, average plasma valacyclovir concentrations observed were 0.5, 0.4,
and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and
in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
Elimination
The pharmacokinetic disposition of acyclovir delivered
by valacyclovir is consistent with previous experience from intravenous and
oral acyclovir. Following the oral administration of a single 1-gram dose of
radiolabeled valacyclovir to 4 healthy subjects, 45.60% and 47.12% of administered
radioactivity was recovered in urine and feces over 96 hours, respectively.
Acyclovir accounted for 88.60% of the radioactivity excreted in the urine. Renal
clearance of acyclovir following the administration of a single 1-gram dose
of VALTREX to 12 healthy volunteers was approximately 255 ± 86 mL/min which
represents 41.9% of total acyclovir apparent plasma clearance.
The plasma elimination half-life of acyclovir typically averaged
2.5 to 3.3 hours in all studies of VALTREX in volunteers with normal renal function.
End-Stage Renal Disease (ESRD)
Following administration of VALTREX to volunteers with ESRD,
the average acyclovir half-life is approximately 14 hours. During hemodialysis,
the acyclovir half-life is approximately 4 hours. Approximately one third of
acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.
Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3
mL/min/1.73 m2, compared to 679.16 ± 162.76 mL/min/1.73 m2
in healthy volunteers.
Reduction in dosage is recommended in patients with renal impairment
(see DOSAGE AND ADMINISTRATION).
Geriatrics
After single-dose administration of 1 gram of VALTREX in healthy
geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared
to 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir
following single- and multiple-dose oral administration of VALTREX in geriatric
volunteers varied with renal function. Dose reduction may be required in geriatric
patients, depending on the underlying renal status of the patient (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Pediatrics
Valacyclovir pharmacokinetics have not been evaluated in pediatric
patients.
Liver Disease
Administration of VALTREX to patients with moderate (biopsy-proven
cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis)
liver disease indicated that the rate but not the extent of conversion of valacyclovir
to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage
modification is not recommended for patients with cirrhosis.
HIV Disease
In 9 patients with advanced HIV disease (CD4 cell counts <150
cells/mm3) who received VALTREX at a dosage of 1 gram 4 times daily
for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different
from that observed in healthy volunteers (see WARNINGS).
DRUG INTERACTIONS
The pharmacokinetics of digoxin was not affected by coadministration
of VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after
a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin
(2 doses of 0.75 mg), single doses of antacids (Al3+ or Mg++),
or multiple doses of thiazide diuretics. Acyclovir Cmax and AUC following a
single dose of VALTREX (1 gram) increased by 8% and 32%, respectively, after
a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after
probenecid (1 gram), or by 30% and 78%, respectively, after a combination of
cimetidine and probenecid, primarily due to a reduction in renal clearance of
acyclovir. These effects are not considered to be of clinical significance in
subjects with normal renal function. Therefore, no dosage adjustment is recommended
when VALTREX is coadministered with digoxin, antacids, thiazide diuretics, cimetidine,
or probenecid in subjects with normal renal function.
Clinical Trials: Herpes Zoster Infections
Two randomized double-blind clinical trials in immunocompetent
adults with localized herpes zoster were conducted. VALTREX was compared to
placebo in patients less than 50 years of age, and to ZOVIRAX in patients greater
than 50 years of age. All patients were treated within 72 hours of appearance
of zoster rash. In patients less than 50 years of age, the median time to cessation
of new lesion formation was 2 days for those treated with VALTREX compared to
3 days for those treated with placebo. In patients greater than 50 years of
age, the median time to cessation of new lesions was 3 days in patients treated
with either VALTREX or ZOVIRAX. In patients less than 50 years of age, no difference
was found with respect to the duration of pain after healing (post-herpetic
neuralgia) between the recipients of VALTREX and placebo. In patients greater
than 50 years of age, among the 83% who reported pain after healing (post-herpetic
neuralgia), the median duration of pain after healing [95% confidence interval]
in days was: 40 [31, 51],
43 [36, 55], and 59 [41, 77] for 7-day VALTREX, 14-day VALTREX, and 7-day ZOVIRAX,
respectively.
Genital Herpes Infections: Initial Episode
Six hundred and forty-three immunocompetent adults with first
episode genital herpes who presented within 72 hours of symptom onset were randomized
in a double-blind trial to receive 10 days of VALTREX 1 gram twice daily (n
= 323) or ZOVIRAX 200 mg 5 times a day (n = 320). For both treatment groups:
the median time to lesion healing was 9 days, the median time to cessation of
pain was 5 days, the median time to cessation of viral shedding was 3 days.
Recurrent Episodes
Three double-blind trials (2 of them placebo-controlled) in
immunocompetent adults with recurrent genital herpes were conducted. Patients
self initiated therapy within 24 hours of the first sign or symptom of a recurrent
genital herpes episode.
In 1 study, patients were randomized to receive 5 days of treatment
with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259). The median
time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus
6 days in the placebo group, and the median time to cessation of viral shedding
in patients with at least 1 positive culture (42% of the overall study population)
was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo
group. The median time to cessation of pain was 3 days in the group receiving
VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy
were replicated in a second trial.
In a third study, patients were randomized to receive VALTREX
500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3
days (and matching placebo twice daily for 2 additional days) (n = 402).
The median time to lesion healing was about 4½ days in both treatment groups.
The median time to cessation of pain was about 3 days in both treatment groups.
Suppressive Therapy: One thousand four hundred
seventy-nine (1,479) immunocompetent adults with a history of 6 or more recurrences
per year were randomized into a double-blind, placebo-controlled study. Outcomes
for the overall study population are shown in Table 1.
|
Table 1. Proportions of Patients Recurrence Free at
6 and 12 Months
|
|
Treatment Arm
|
6 Months
|
12 Months
|
|
VALTREX 1 gram q.d. (n = 269)
|
ZOVIRAX 400 mg b.i.d. (n = 267)
|
Placebo (n = 134)
|
VALTREX 1 gram q.d. (n = 269)
|
ZOVIRAX 400 mg b.i.d. (n = 267)
|
Placebo (n = 134)
|
|
|
|
Recurrence free (%)
|
55
|
54
|
7
|
34
|
34
|
4
|
|
Recurrences(%)
|
35
|
36
|
83
|
46
|
46
|
85
|
|
Unknowns (%)
|
10
|
10
|
10
|
19
|
19
|
10
|
Subjects with 9 or fewer recurrences per year showed comparable
results with VALTREX 500 mg once daily.
Cold Sores (Herpes Labialis)
Two double-blind, placebo-controlled clinical trials were
conducted in 1,856 healthy adults and adolescents (³12
years old) with a history of recurrent cold sores.
Patients self initiated therapy at the earliest symptoms and prior to any signs
of a cold sore. The majority of patients initiated treatment within 2 hours
of onset of symptoms. Patients were randomized to VALTREX 2 grams twice daily
on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1
followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
The mean duration of cold sore episodes was about 1 day shorter
in treated subjects as compared to placebo. The 2-day regimen did not offer
additional benefit over the 1-day regimen.
No significant difference was observed between subjects receiving
VALTREX or placebo in the prevention of progression of cold sore lesions beyond
the papular stage.
MICROBIOLOGY
Mechanism of Antiviral Action
Valacyclovir hydrochloride is rapidly converted to acyclovir
which has demonstrated antiviral activity against herpes simplex virus types
1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in vitro and in
vivo.
The inhibitory activity of acyclovir is highly selective due
to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV.
This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide
analogue. The monophosphate is further converted into diphosphate by cellular
guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro,
acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished
in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation
and termination of the growing viral DNA chain, and 3) inactivation of the viral
DNA polymerase. The greater antiviral activity of acyclovir against HSV compared
to VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities
The quantitative relationship between the in vitro susceptibility
of herpesviruses to antivirals and the clinical response to therapy has not
been established in humans, and virus sensitivity testing has not been standardized.
Sensitivity testing results, expressed as the concentration of drug required
to inhibit by 50% the growth of virus in cell culture (IC50), vary
greatly depending upon a number of factors. Using plaque-reduction assays, the
IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5
mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50
for acyclovir against most laboratory strains and clinical isolates of VZV ranges
from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka
vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Drug Resistance
Resistance of HSV and VZV to acyclovir can result from
qualitative and quantitative changes in the viral TK and/or DNA polymerase.
Clinical isolates of VZV with reduced susceptibility to acyclovir have been
recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV
have been recovered.
Resistance of HSV and VZV to acyclovir occurs by the same mechanisms.
While most of the acyclovir-resistant mutants isolated thus far from immunocompromised
patients have been found to be TK-deficient mutants, other mutants involving
the viral TK gene (TK partial and TK altered) and DNA polymerase have also been
isolated. TK-negative mutants may cause severe disease in immunocompromised
patients. The possibility of viral resistance to valacyclovir (and therefore,
to acyclovir) should be considered in patients who show poor clinical response
during therapy.
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