Herpes Simplex Virus Type 1 (HSV-1). [1]

By deacetylation, famciclovir metabolizes into BRL 42359, which oxidizes to penciclovir[3].

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The prodrug Famciclovir is converted to its active form penciclovir (PCV). The antiviral activity of PCV against the clinical HSV-1 strain (HSV-1-511) was evaluated by plaque reduction assay. The mean EC50 (effective concentration for 50% plaque reduction) of PCV was 0.07 ± 0.02 μg/mL in rabbit testes cells (RTP) and 0.08 ± 0.02 μg/mL in BALB/c 3T6 mouse cells, indicating comparable in vitro potency against this strain. [1]

Necrotic hepatitis mice can be effectively cured by famciclovir (50–400 mg/kg; p.o. three times per day for a total of 10 doses)[1].

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In a juvenile mouse model of disseminated HSV-1 infection (induced by intravenous inoculation of a highly virulent clinical isolate), oral treatment with Famciclovir starting 2 days post-infection (when microscopic liver lesions were already present) showed significant protective effects. At a daily dose of 50 mg/kg (divided into three doses every 8 hours for 3 days), FCV significantly reduced the incidence of macroscopic necrotic hepatitis on day 6 post-infection (p<0.001) compared to untreated controls. [1]
At the same daily dose of 50 mg/kg, Famciclovir also significantly reduced mortality (p<0.001) over a 21-day observation period. This protective effect against death was significantly better (p<0.05) than that achieved by valaciclovir at the same 50 mg/kg/day dose. Treatment with higher doses of FCV (100, 200, 400 mg/kg/day) further reduced hepatitis incidence and mortality, with 200 and 400 mg/kg/day preventing all macroscopic liver lesions and deaths in the treated groups. [1]
In surviving mice treated with FCV at 100 mg/kg/day, HSV DNA was still detectable by PCR in the brain stem of some animals (3 out of 8) on day 21 post-infection, suggesting possible establishment of latency or residual viral genomes. [1]

Penciclovir is selectively phosphorylated in herpesvirus-infected cells by viral thymidine kinase to penciclovir monophosphate, then to diphosphate and triphosphate forms. Penciclovir triphosphate inhibits viral DNA polymerase, thereby inhibiting viral DNA synthesis. The phosphorylation process is more efficient in virus-infected cells than in uninfected host cells. The intracellular half-life of penciclovir triphosphate is longer than that of acyclovir triphosphate, contributing to prolonged antiviral activity.[4]

Plaque Inhibition Assay: The in vitro susceptibility of the HSV-1-511 strain to penciclovir (the active metabolite of Famciclovir) was determined. Briefly, cell cultures (BALB/c 3T6 or rabbit testes cells) in flasks were infected with a virus suspension yielding about 50 plaques per flask. After a 1-hour adsorption period, the inoculum was removed and the cells were overlaid with a nutrient medium containing various concentrations of the antiviral drug. The cultures were then incubated at 37°C for 72 hours. After incubation, the cells were fixed and stained with crystal violet, and the number of plaques was counted microscopically. The drug concentration required to reduce the plaque count by 50% (EC50) was determined from dose-response curves. [1]

Animal Model: Four- to five-week-old Balb/c mice with HSV-1 infection[1]
Dosage: 50, 100, 200 and 400 mg/kg
Administration: Oral gavage; 50-400 mg/kg per day divided into three doses given every 8 h; for total 10 doses
Result: significantly decreased the daily incidence of hepatitis when administered at a dose of 50 mg/kg; however, the treatment group receiving doses of 50 and 100 mg/kg was unable to isolate the infectious virus.

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Mouse Model of Disseminated HSV-1 Infection and Treatment: Four- to five-week-old Balb/c mice weighing 18-22 g were infected intravenously on day 0 with a lethal dose of HSV-1-511. Treatment with Famciclovir was initiated on day 2 post-infection (a time point when microscopic liver lesions are already present, simulating clinical diagnosis) and continued for 3 days, for a total of 10 doses. The drug was administered orally by gavage. It was dissolved in phosphate-buffered saline (PBS), and a volume of 0.2 mL of the solution was given per mouse per dose. The daily dose was divided into three equal parts administered every 8 hours. Doses tested included 50, 100, 200, and 400 mg/kg/day. Mice were monitored twice daily for 21 days for signs of encephalitis and death. To assess effects on hepatitis, half of the animals from each group were sacrificed on day 6 post-infection (one day after treatment ended) to examine the liver surface for macroscopic necrotic lesions. The remaining mice were observed for mortality until day 21. [1]

Absorption, Distribution and Excretion
77% Active tubular secretion promotes renal clearance of penciclovir. 1.08 ± 0.17 L/kg [Single intravenous injection of 400 mg penciclovir in healthy male subjects, 1 hour after intravenous infusion] 36.6 ± 6.3 L/hr [Healthy males] 0.48 ± 0.09 L/hr/kg [Healthy males] Following oral administration of famciclovir to lactating rats, the concentration of penciclovir in breast milk was higher than in plasma. It is unclear whether penciclovir can cross the placenta or distribute into human breast milk. In 7 patients with herpes zoster, after a single oral administration of 500 mg famciclovir, the AUC (mean ± standard deviation), Cmax, and tmax were 12.1 ± 1.7 μg·hr/mL, 4.0 ± 0.7 μg/mL, and 0.7 ± 0.2 hours, respectively. Compared with healthy volunteers, patients with herpes zoster had approximately 35% higher AUC for penciclovir. This difference may be partly related to differences in renal function between the two groups. Following a single oral dose of 500 mg famciclovir in 109 healthy male volunteers, the renal clearance of penciclovir was 27.7 ± 7.6 L/hr. Active tubular secretion contributes to the renal excretion of penciclovir. For more complete data on the absorption, distribution, and excretion of famciclovir (11 items in total), please visit the HSDB record page. Metabolism/Metabolites Hepatic Metabolism: Famciclovir is deacetylated and oxidized to penciclovir. In cells infected with HSV-1, HSV-2, or VZV, penciclovir is phosphorylated to penciclovir triphosphate (the active metabolite). The inactive metabolite 6-deoxypenciclovir is converted to penciclovir by aldehyde oxidase. Famciclovir is not metabolized by CYP enzymes. Following oral administration, famciclovir undergoes deacetylation and oxidation to generate penciclovir. Inactive metabolites include 6-deoxypenciclovir, monoacetylated penciclovir, and 6-deoxymonoacetylated penciclovir (representing 5%, <0.5%, and <0.5% of the urinary dose, respectively). Famciclovir is virtually undetectable in plasma or urine. An in vitro study using human liver microsomes indicated that cytochrome P450 does not play a significant role in famciclovir metabolism. The conversion of 6-deoxypenciclovir to penciclovir is catalyzed by aldehyde oxidase.

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Biological Half-Life
10 hours
Following oral administration of famciclovir, the elimination half-life of penciclovir is 1.6–3 hours. In cells infected with herpes simplex virus (HSV)-1 or HSV-2, the intracellular half-life of penciclovir triphosphate was 10 hours and 20 hours, respectively; the intracellular half-life in cells infected with varicella-zoster virus (VZV) was 7–14 hours.
In 48 healthy male volunteers, the plasma elimination half-life after intravenous injection of penciclovir was 2.0 ± 0.3 hours; in 124 healthy male volunteers, the plasma elimination half-life after oral administration of 500 mg famciclovir was 2.3 ± 0.4 hours. In 17 patients with herpes zoster, the plasma elimination half-life was 2.8 ± 1.0 hours after a single dose; after multiple doses, the plasma elimination half-life was 2.7 ± 1.0 hours.

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Literature indicates that famciclovir is readily absorbed after oral administration and is effectively converted to its active form, penciclovir (PCV), with a bioavailability of 77%. [1] A key feature of penciclovir triphosphate (the intracellular active form) is that it has a longer duration of action within HSV-infected cells compared to acyclovir triphosphate, which may allow for a reduction in the frequency of administration. [1]

Hepatotoxicity
The incidence of elevated serum transaminases during oral famciclovir treatment is low. In a pooled analysis of patients receiving long-term suppressive therapy, 3.2% of patients in the famciclovir group experienced ALT elevations more than twice the normal value, compared to 1.5% in the placebo group. These elevations were transient, asymptomatic, and resolved spontaneously without dose adjustment. Since approval, the sponsor has received reports of cholestatic jaundice, but no published case reports have been received. Therefore, clinically significant liver disease caused by famciclovir, if it occurs, is certainly very rare. Probability score: E (unlikely to be the cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Since there is no published experience regarding the use of famciclovir during lactation, alternative medications may be preferred, especially in breastfed newborns or preterm infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding rate 20-25%

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Interactions 6-Deoxypenciclovir is converted to penciclovir by aldehyde oxidase. Interactions may occur with other drugs metabolized by and/or inhibiting this enzyme. In vitro clinical interaction studies with the aldehyde oxidase inhibitors cimetidine and promethazine showed that the interaction of famciclovir with these drugs had no significant effect on penciclovir production. Raloxifene, a potent in vitro aldehyde oxidase inhibitor, may reduce penciclovir production. However, no clinical drug interaction studies have been conducted to determine the extent of the interaction between penciclovir and raloxifene.
Pharmacokinetic interactions may occur with other drugs metabolized by aldehyde oxidase.
When used in combination with other drugs that are actively cleared by renal tubules (e.g., probenecid), plasma penciclovir concentrations may be elevated.

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Fanciclovir is well tolerated, with an adverse reaction profile similar to placebo and acyclovir. The most common adverse reactions are headache, nausea, and diarrhea. No clinically significant pharmacokinetic interactions were observed with allopurinol, digoxin, cimetidine, theophylline, or zidovudine. In preclinical studies, high doses of fanciclovir caused reversible, dose-dependent testicular toxicity in dogs and mice, but a clinical study in men showed no significant effect on sperm parameters. [4]

[1]. Wutzler P, Ulbricht A, Färber I. Antiviral efficacies of famciclovir, valaciclovir, and brivudin in disseminated herpes simplex virus type 1 infection in mice. Intervirology. 1997;40(1):15-21.

[2]. administration are replication defective. Hepatology. 1998 Feb;27(2):628-33.

[3]. Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6 beta-hydroxylation of testosterone in human liver microsomes. Drug Metab Dispos. 1993 Jan-Feb;21(1):18-23.

[4]. Drugs. 1995 Aug;50(2):396-415.

Therapeutic Uses

Antiviral Drugs
Oral famciclovir is used to treat acute localized herpes zoster (commonly known as "shingles" or "herpes zoster"). /Included on the US product label/
Oral famciclovir is used to treat recurrent mucocutaneous herpes simplex virus (HSV) infection (HSV-1 and HSV-2) in adults with HIV infection. /Included on the US product label/
Famciclovir has been used to treat chronic hepatitis B virus (HBV) infection in a small number of patients. /Not included on the US product label/
For more complete therapeutic use data for famciclovir (12 types in total), please visit the HSDB record page.

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Drug Warnings
These/adverse events have been reported during postmarketing use of famciclovir. Because these events are from an indeterminate number of voluntary reporting populations, their frequency cannot always be reliably estimated or a causal relationship with drug exposure can not always be established: Blood and Lymphatic Disorders: Thrombocytopenia. Hepatobiliary diseases: abnormal liver function, cholestatic jaundice. Nervous system diseases: dizziness, somnolence. Psychiatric diseases: confusion (including delirium, disorientation, and confusion primarily occurring in the elderly), hallucinations. Skin and subcutaneous tissue diseases: urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g., facial, eyelid, periorbital, and pharyngeal edema). The manufacturer recommends that for patients with impaired renal function, the dosing interval of famciclovir should be carefully adjusted to prevent drug accumulation while maintaining adequate plasma concentrations of the active metabolite penciclovir. In clinical trials of herpes zoster or genital herpes, 1.4% to 2.4% of patients treated with famciclovir experienced elevated serum ALT (SGPT) levels. Elevated serum alkaline phosphatase, total bilirubin, and albumin levels were rarely observed in patients treated with this drug in clinical trials of herpes zoster or genital herpes. In a large, controlled clinical trial of famciclovir, the most common gastrointestinal adverse reaction was nausea, occurring in approximately 13% of patients in the drug group (compared to 11.6% in the placebo group). In clinical trials of herpes zoster or genital herpes, less than 1% of patients discontinued famciclovir due to nausea. In a large, controlled clinical trial of herpes zoster, approximately 8% of patients (5% in the placebo group) reported diarrhea, and approximately 5% (3.4% in the placebo group) reported vomiting. Discontinuation of famciclovir due to vomiting was rare in clinical trials of herpes zoster or genital herpes. In clinical trials of herpes zoster, patients receiving famciclovir treatment experienced symptoms such as constipation, anorexia, abdominal pain, bloating, and indigestion. There has been a reported case of a kidney transplant recipient concurrently receiving cyclosporine treatment developing acute necrotizing hemorrhagic pancreatitis and ultimately dying after receiving famciclovir treatment for severe hepatitis B virus infection; however, a causal relationship between this case and famciclovir has not been established. In clinical studies, nausea, diarrhea, vomiting, or abdominal pain were reported in 11%, 7%, 5%, and 3% of HIV-infected patients receiving famciclovir, respectively. For more complete data on famciclovir (12 total), please visit the HSDB record page. Pharmacodynamics: Famciclovir is a prodrug that is rapidly biotransformed into the active antiviral compound penciclovir. Penciclovir is an antiviral drug with inhibitory activity against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV). Therefore, it selectively inhibits herpesvirus DNA synthesis and replication. Famciclovir is an oral prodrug of penciclovir (PCV), a novel antiviral drug with significant activity against HSV and VZV. [1]
In the mouse model discussed, oral administration of famciclovir (at doses of 50 mg/kg/day and above) significantly halted the progression of existing liver tissue damage (gross necrosis). [1]
At effective doses (50 and 100 mg/kg/day), famciclovir treatment also completely cleared infectious virus from the liver within a 3-day treatment period. [1]
This study suggests that famciclovir was more effective than valacyclovir in this model, possibly due to the long-term inhibition of viral replication by penciclovir triphosphate after discontinuation of the drug. [1]

C14H19N5O4

321.33176

321.143

C, 52.33; H, 5.96; N, 21.79; O, 19.92

104227-87-4

Famciclovir-d4;1020719-42-9

3324

White to off-white solid powder

1.4±0.1 g/cm3

550.2±60.0 °C at 760 mmHg

102-104°C

286.6±32.9 °C

0.0±1.5 mmHg at 25°C

1.628

-0.67

1

8

9

23

404

0

NC1=NC=C2N=CN(CCC(COC(C)=O)COC(C)=O)C2=N1

GGXKWVWZWMLJEH-UHFFFAOYSA-N

InChI=1S/C14H19N5O4/c1-9(20)22-6-11(7-23-10(2)21)3-4-19-8-17-12-5-16-14(15)18-13(12)19/h5,8,11H,3-4,6-7H2,1-2H3,(H2,15,16,18)

[2-(acetyloxymethyl)-4-(2-aminopurin-9-yl)butyl] acetate

Famvir, BRL-42810; BRL42810; BRL 42810

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 64~100 mg/mL ( 199.16~311.21 mM )
Water : 64 mg/mL
Ethanol : ~48 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 120 mg/mL (373.45 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)