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Denavir (Penciclovir Sodium) - Description and Clinical Pharmacology

 
 



DESCRIPTION

DENAVIR (penciclovir) cream 1% contains penciclovir, an antiviral agent active against herpes viruses. DENAVIR is available for topical administration as a 1% white cream. Each gram of DENAVIR contains 10 mg of penciclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water and white petrolatum.
Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. Its molecular formula is C10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative and has the following structure:

Figure 1: Structural Formula of Penciclovir

Figure 1: Structural Formula of Penciclovir

Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL.  Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62).

CLINICAL PHARMACOLOGY

Mechanism of Action

Penciclovir is an antiviral agent active against herpes viruses [see Microbiology ].

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.

Microbiology

Mechanism of Action :  The antiviral compound penciclovir has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2).  In cells infected with HSV-1 or HSV-2, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate.   Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV 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 and 20 hours in HSV-2 infected cells grown in culture.  However, the clinical significance of the intracellular half-life is unknown.

Antiviral Activity:  In cell culture studies, penciclovir has antiviral activity against the following herpes viruses:  HSV-1 and HSV-2. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1 and HSV-2 were 2 µM (range 1.2 to 2.4 µM, n=7) and 2.6 µM (range 1.6 to 11 µM, n=6), respectively.

Resistance :  Penciclovir-resistant mutants of HSV can result from mutations in viral thymidine kinase (TK) and DNA polymerase genes.  Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered).  The median EC50 values observed in a plaque reduction assays with penciclovir resistant HSV-1 and HSV-2 were 69 µM (range 14 to 115 µM, n=6) and 46 µM (range 4 to > 395 µM, n=9), respectively.  The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Cross-resistance :   Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir-resistant mutants that are deficient in viral thymidine kinase (TK negative) are also resistant to penciclovir.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In clinical trials, systemic drug exposure following topical administration of penciclovir cream was negligible, as the penciclovir content of all plasma and urine samples was below the limit of assay detection (0.1 mcg/mL and 10 mcg/mL, respectively).  However, for the purpose of inter-species dose comparisons presented in the following sections, an assumption of 100% absorption of penciclovir from the topically applied product has been used.  Based on the use of the maximal recommended topical dose of penciclovir of 0.05 mg/kg/day and an assumption of 100% absorption, the maximum theoretical plasma AUC0-24 hrs for penciclovir is approximately 0.129 mcg.hr/mL.

Carcinogenesis:  Two-year carcinogenicity studies were conducted with famciclovir (the oral prodrug of penciclovir) in rats and mice.  An increase in the incidence of mammary adenocarcinoma (a common tumor in female rats of the strain used) was seen in female rats receiving 600 mg/kg/day (approximately 395x the maximum theoretical human exposure to penciclovir following application of the topical product, based on area under the plasma concentration curve comparisons [24 hr. AUC]).  No increases in tumor incidence were seen among male rats treated at doses up to 240 mg/kg/day (approximately 190x the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100x the maximum theoretical human AUC for penciclovir).

Mutagenesis:  When tested in vitro, penciclovir did not cause an increase in gene mutation in the Ames assay using multiple strains of S. typhimurium or E. coli (at up to 20,000 mcg/plate), nor did it cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 mcg/mL).  However, an increase in clastogenic responses was seen with penciclovir in the L5178Y mouse lymphoma cell assay (at doses ≥1000 mcg/mL) and, in human lymphocytes incubated in vitro at doses ≥250 mcg/mL.  When tested in vivo, penciclovir caused an increase in micronuclei in mouse bone marrow following the intravenous administration of doses ≥500 mg/kg (≥810x the maximum human dose, based on body surface area conversion).

Impairment of Fertility:  Testicular toxicity was observed in multiple animal species (rats and dogs) following repeated intravenous administration of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately 1155 and 3255x the maximum theoretical human AUC).  Testicular changes seen in both species included atrophy of the seminiferous tubules and reductions in epididymal sperm counts and/or an increased incidence of sperm with abnormal morphology or reduced motility.  Adverse testicular effects were related to an increasing dose or duration of exposure to penciclovir.  No adverse testicular or reproductive effects (fertility and reproductive function) were observed in rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845x the maximum theoretical human AUC, respectively).  Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260x the maximum human dose [BSA]).

There was no evidence of any clinically significant effects on sperm count, motility or morphology in 2 placebo-controlled clinical trials of Famvir® (famciclovir [the oral prodrug of penciclovir], 250 mg b.i.d.; n=66) in immunocompetent men with recurrent genital herpes, when dosing and follow-up were maintained for 18 and 8 weeks, respectively (approximately 2 and 1 spermatogenic cycles in the human).

CLINICAL STUDIES

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.

HOW SUPPLIED/STORAGE AND HANDLING

DENAVIR is supplied in a 1.5 gram and 5 gram tube containing 10 mg of penciclovir per gram.
NDC 50816-624-01
NDC 40076-624-05
Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

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