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
Denavir Pharmacology, Pharmacokinetics, Studies, Metabolism - Penciclovir
Denavir Pharmacology, Pharmacokinetics, Studies, Metabolism - Penciclovir
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of Antiviral Activity: The antiviral compound penciclovir
has in vitro inhibitory activity against herpes simplex virus types
1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2 viral thymidine
kinase phosphorylates penciclovir to a monophosphate form which, in turn,
is converted to penciclovir triphosphate by cellular kinases. In vitro
studies demonstrate that penciclovir triphosphate inhibits HSV polymerase
competitively with deoxyguanosine triphosphate. Consequently, herpes viral
DNA synthesis and, therefore, replication are selectively inhibited.
Antiviral Activity in vitro and in vivo: In cell
culture studies, penciclovir has antiviral activity against HSV-1 and
HSV-2. Sensitivity test results, expressed as the concentration of the
drug required to inhibit growth of the virus by 50% (IC50)
or 99% (IC99) cell culture, vary depending upon a number of
factors, including the assay protocols. See Table 1.
| Table 1 |
| Method of Assay |
Virus Type |
Cell Type |
IC50
(mcg/mL) |
IC99
(mcg/mL) |
| Plaque Reduction |
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 Reduction |
HSV-1 (c.i.) |
MRC-5 |
|
0.4-0.5 |
| HSV-2 (c.i.) |
MRC-5 |
|
0.6-0.7 |
| DNA Synthesis Inhibition |
HSV-1 (SC16) |
MRC-5 |
0.04 |
|
| HSV-2 (MS) |
MRC-5 |
0.05 |
|
(c.i.) = clinical isolates. The latent state of any herpes virus is not
known to respond to any antiviral therapy.
Drug Resistance: Penciclovir-resistant mutants of HSV can result
from qualitative changes in viral thymidine kinase or DNA polymerase.
The most commonly encountered acyclovir-resistant mutants that are deficient
in viral thymidine kinase are also resistant to penciclovir.
Pharmacokinetics
Measurable penciclovir concentrations were not detected in plasma or
urine of healthy male volunteers (n= 12) following single or repeat application
of the 1% cream at a dose of 180 mg penciclovir daily (approximately 67
times the estimated usual clinical dose).
Pediatric Patients: The systemic absorption of penciclovir following
topical administration has not been evaluated in patients <18 years of
age.
CLINICAL TRIALS
Denavir was studied in two double-blind placebo (vehicle)-controlled
trials for the treatment of recurrent herpes labialis in which otherwise
healthy adults were randomized to either Denavir or placebo. Therapy
was to be initiated by the subjects within 1 hour of noticing signs or
symptoms and continued for 4 days, with application of study medication
every 2 hours while awake. In both studies, the mean duration of lesions
was approximately one-half-day shorter in the subjects treated with Denavir
(N=1,516) as compared to subjects treated with placebo ( N=1,541) (approximately
4.5 days versus 5 days, respectively). The mean duration of lesion pain
was also approximately one-half-day shorter in the Denavir group
compared to the placebo group.
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