Penciclovir

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that penciclovir is expected to have very high mobility in soil(SRC). Volatilization of penciclovir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-32 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Penciclovir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A biodegradation half-life of 3.4 hours using activated sludge(4) indicates that biodegradation may be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that penciclovir is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.5X10-32 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of -1.14(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A biodegradation half-life of 3.4 hours using activated sludge(7) indicates that biodegradation may be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), penciclovir, which has an estimated vapor pressure of 3.0X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase penciclovir may be removed from the air by wet and dry deposition(SRC). Penciclovir contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be suscetible to direct photolysis by sunlight(SRC).

There is no information on whether penciclovir is excreted in human milk after topical administration. However, following oral administration of famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma.

Following oral administration of famciclovir to lactating rats, penciclovir was distributed into breast milk at concentrations higher than those observed in plasma.

Antiviral drugs have been recently recognized as one of the emerging contaminants in the environment. These are discharged after therapeutic use through human excretion. Effluent containing high concentration of antiviral drugs discharged from production facilities is also a cause of concern to nearby aquatic bodies. There is an increased interest in their removal because they are highly bioactive. Some antiviral drugs are resistant to conventional methods of degradation, and there is a risk of development of antiviral resistance in humans and animals if exposed repeatedly for long periods. To date, the potential human, animal, and ecological risks associated with the discharge of these antiviral compounds to the environment are not well documented. This study presents a brief summary on occurrence, ecotoxicological risks, and physicochemical properties of antiviral drugs in the environment. The needs regarding removal, disposal, and treatment of antiviral drugs are also addressed(1). /Antiviral drugs/

Penciclovir was tested for in raw and treated wastewater from two conventional German waste water treatment plants. Plant 1 activated sludge hydraulic retention time and sludge retention time of 12 hrs and 10-12 days respectively; treating 330,000 population equivalents, daily flow rate of 60,000 cu m. Penciclovir was present at 42.8 ng/L in the effluent and below the limit of quantification (5 ng/L) in the effluent, a >94% elimination (grab samples). Plant 2 treats 200,000 cu m daily serving 1,350,000 population equivalents and incorporates primary aerobic, secondary anaerobic treatments. Penciclovir was present at 19,5 ng/L in the influent and below the limit of quantification (5 ng/L) in the effluent, a >87% elimination (24hr composite samples). (1)

Using a structure estimation method based on molecular connectivity indices(1), the Koc of penciclovir can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that penciclovir is expected to have very high mobility in soil.

/HUMAN EXPOSURE STUDIES/ 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).

/SIGNS AND SYMPTOMS/ Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose.

/GENOTOXICITY/ ...Penciclovir did not cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 ug/mL).

/GENOTOXICITY/ An increase in clastogenic responses was seen with penciclovir in human lymphocytes incubated in vitro at doses >/=250 ug/mL.

/GENOTOXICITY/ In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation at a concentration of 250 ug/mL.

Penciclovir's production and administration as an antiviral(1) may result in its release to the environment through various waste streams(SRC). The administration of famciclovir is also a source of penciclovir, since pensisclovir is a human metabolite of famciclovir(2).

AEROBIC: Penciclovir was biodegraded in activated sludge, with a half-life 3.4 hrs and first-order rate constants in relation to the amount of suspended solids of 7.6/day. The main transformation pathway was the oxidation of one of the primary hydroxyl groups to the respective carboxylic moiety(1). There are eight unspecified products, one of which was shown to result in inactivation of enzymes and mutagensis in the human body(2).

An estimated BCF of 3 was calculated in fish for penciclovir(SRC), using an estimated log Kow of -1.14(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for penciclovir is estimated as 9.5X10-32 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that penciclovir is expected to be essentially nonvolatile from water and moist soil surfaces(2). Penciclovir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-17 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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 395 times 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 190 times the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100 times the maximum theoretical human AUC for penciclovir).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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 3255 times 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 845 times the maximum theoretical human AUC, respectively).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260 times the maximum human dose [BSA]).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No adverse effects on the course and outcome of pregnancy or on fetal development were noted in rats and rabbits following the intravenous administration of penciclovir at doses of 80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and 18 mg/kg/day for the rat and rabbit, respectively, based on body surface area conversion; the body surface area doses being 260 and 35 times the maximum recommended dose following topical application of the penciclovir cream).

For more Non-Human Toxicity Excerpts (Complete) data for Penciclovir (13 total), please visit the HSDB record page.

Penciclovir is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Penciclovir contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to penciclovir may occur through inhalation and dermal contact with this compound at workplaces where penciclovir is produced or used. Exposure to penciclovir among the general population may be limited to those administered the drug. (SRC)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including penciclovir sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Penciclovir sodium/

Viral DNA polymerase inhibitor

MEDICATION

THERAPEUTIC CATEGORY: Antiviral

Use (kg; approx.) in Germany (2009): >10

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: cetomacrogol 1000 BP, cetostearyl alcohol, mineral oil, propylene glycol, purified water and white petrolatum.

Vectavir