Denavir (Penciclovir Sodium) - Description and Clinical Pharmacology

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) in 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	IC 50 (mcg/mL)	IC 99 (mcg/mL)
Plaque Reduction	HSV-1 (c.i.) HSV-1 (c.i.) HSV-2 (c.i.) HSV-2 (c.i.)	MRC-5 WISH MRC-5 WISH	0.2-0.6 0.04-0.5 0.9-2.1 0.1-0.8
Virus Yield Reduction	HSV-1 (c.i.) HSV-2 (c.i.)	MRC-5 MRC-5		0.4-0.5 0.6-0.7
DNA Synthesis Inhibition	HSV-1 (SC16) HSV-2 (MS)	MRC-5 MRC-5	0.04 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.