Famciclovir

Description

Famciclovir, an effective oral prodrug of the antiviral penciclovir, was launched in the UK and shortly after in the U.S.A. for the treatment of shingles (herpes zoster). As the diacetyl ester of the 6-deoxy- penciclovir, famciclovir has significantly improved oral absorption. It is converted to penciclovir in vivo with a bioavailability of 41 % in rats. Penciclovir is phosphorylated, and hence activated onty in herpesvirus infected cells. This stable metabolite, penciclovir-triphosphate, is a strong inhibitor of herpesvirus DNA polymerases and of viral DNA synthesis with long lasting effects. The high selectivity of famciclovir/penciclovir to herpes family of viruses and their rather low toxicity may make this agent superior to other existing drugs.

Chemical Properties

Off-White Powder

Originator

SmlthKline Beecham (United Kingdom)

Uses

Used as an antiviral. Prodrug of Penciclovir (P221500).

Uses

These Secondary Standards are qualified as Certified Reference Materials. These are suitable for use in several analytical applications including but not limited to pharma release testing, pharma method development for qualitative and quantitative analyses, food and beverage quality control testing, and other calibration requirements.

Uses

sterol absorption inhibitor.

Famciclovir (Famvir) a synthetic acyclic purine analog derived from guanine. It is the diacetyl ester (prodrug) of penciclovir, which exhibits no antiviral activity until hydrolyzed to penciclovir and its active metabolites. It is indicated for the management of acute herpes zoster infections. It has been shown to relieve acute symptoms as well as to shorten the duration of postherpetic neuralgia. It is also used for the treatment or suppression of recurrent episodes of genital herpes in immunocompetent patients and in the treatment of recurrent herpes simplex types 1 and 2 infections in patients with human immunodeficiency virus.

Definition

ChEBI: 2-Amino-9H-purine in which the hydrogen at position 9 is substituted by a 4-acetoxy-3-(acetoxymethyl)but-1-yl group. A prodrug of the antiviral penciclovir, it is used for the treatment of acute herpes zoster (shingles), for the treatmen or suppression of recurrent genital herpes in immunocompetent patients and for the treatment of recurrent mucocutaneous herpes simplex infections in HIV infected patients.

Indications

Famciclovir (Famvir) is the diacetyl ester prodrug of the acyclic guanosine analogue 6-deoxypenciclovir (Denavir).

Manufacturing Process

A suspension 1.0 mmol of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6- chloropurine (was synthesized from 2-amino-6-chloropurine and acetic acid 2- acetoxymethyl-4-hydroxybutyl ester) and 400 mmol 10% palladium-oncharcoal in methanol containing ammonium formate was heated under reflux for 30 min. The mixture was allowed to cool, filtered and the solvent removed. The residue was taken up in water and solution extracted twice with chloroform. The organic layers were combined, dried (magnesium sulfate) and the solvent removed to afford 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2- amino-6-purine, yield 90%, m.p. 102-104°C.

brand name

Famvir (Novartis);Famvlr.

Therapeutic Function

Antiviral

General Description

Famciclovir is a diacetyl prodrug of penciclovir.As a prodrug,it lacks antiviral activity. Penciclovir, 9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine, is an acyclic guanine nucleoside analog. The structure is similar to that of acyclovir,except in penciclovir, a side chain oxygen has beenreplaced by a carbon atom and an extra hydroxymethylgroup is present.
VSV-infected cells, penciclovir is first phosphorylated byviral thymidine kinase41 and then further elaborated to thetriphosphate by host cell kinases. Penciclovir triphosphate isa competitive inhibitor of viral DNA polymerase. The pharmacokineticparameters of penciclovir are quite different fromthose of acyclovir. Although penciclovir triphosphate is about100-fold less potent in inhibiting viral DNA polymerase thanacyclovir triphosphate, it is present in the tissues for longerperiods and in much higher concentrations than acyclovir.

Biological Activity

Famciclovir has much greater oral bioavailability (77%) than its active metabolite, penciclovir (5%). Upon oral administration of famciclovir, rapid, extensive, and consistent absorption occurs in the wall of the upper intestine. The consistent absorption is in part due to the drug’s prolonged stability in duodenal contents. Famciclovir undergoes first-pass metabolism by the intestinal wall and liver, where deacetylation and oxidation occur, subsequently forming the major active metabolite, penciclovir. In healthy male subjects the plasma elimination half-life of penciclovir is approximately 2 hours following both intravenous doses of penciclovir and an oral dose of famciclovir (125, 250, 500, or 750 mg). Over the concentration range of 0.1–20 mg/ml, penciclovir is o20% bound to plasma proteins.

Biochem/physiol Actions

Famciclovir is an antiretroviral guanosine analog used to treat herpesvirus infections and hepatitis B. Famciclovir is rapidly converted to penciclovir. Viral thymidine kinase phosphorylates penciclovir to a monophosphate form that celular kinases convert in turn to penciclovir triphosphate. Penciclovir triphosphate competitively inhibits viral DNA polymerase and thus viral replication. Prolonged administration can lead to resistance; it is often manifested as selection of pre-existing resistant strains with mutations in the reverse transcriptase domain of the DNA polymerase gene.

Mechanism of action

Famciclovir is an oral prodrug of the antiviral agent penciclovir (diacetyl 6-deoxy analog of penciclovir). It is effectively metabolized in the liver and the intestinal wall, where two acetyl groups are removed to give 6-deoxy-penciclovir, which is then oxidized at the 6-position of the purine ring to form penciclovir. The mode of action of penciclovir is broadly similar to that of aciclovir. Like aciclovir, the affinity of penciclovir for viral DNA polymerases is markedly higher than for host cell DNA polymerases. In herpesvirusinfected cells the virus-specific TK enzyme efficiently converts penciclovir to penciclovir monophospate, which is then converted to penciclovir triphosphate (the active metabolite) by host cell enzymes. Penciclovir triphosphate inhibits viral replication through competitive inhibition of viral DNA polymerase with the natural substrate deoxyguanosine triphosphate (dGTP).

Mechanism of action

Famciclovir is a synthetic purine nucleoside analogue related to guanine. It is the diacetyl 6-deoxy ester of penciclovir, which is structurally related to ganciclovir. Its pharmacological and microbiological activities are similar to those of acyclovir. Famciclovir is a prodrug of penciclovir, which is formed in vivo by hydrolysis of the acetyl groups and oxidation at the 6-position by mixed function oxidases. Penciclovir and its metabolite penciclovir triphosphate possess antiviral activity resulting from inhibition of viral DNA polymerase.

Pharmacokinetics

Famciclovir can be given with or without food. The most common adverse effects are headache and GI disturbances. Concomitant use of famciclovir with probenecid results in increased plasma concentrations of penciclovir. The recommended dose of famciclovir is 500 mg every 8 hours for 7 days. The absolute bioavailability of famciclovir is 77%, and the area under plasma concentration–time curve (AUC) is 86 μg/mL. Famciclovir with digoxin increased plasma concentration of digoxin to 19% as compared to digoxin given alone.

Pharmacology

Famciclovir (Famvir) undergoes extensive first-pass metabolism to penciclovir after oral administration. Penciclovir is another nucleoside analog that has a mechanism of action similar to that of acyclovir. Compared with oral acyclovir, famciclovir has improved bioavailability as well as a significantly prolonged intracellular half-life, allowing for less frequent dosing. Valacyclovir and famciclovir are similar in their high absorption, bioavailability, renal elimination, minimal drug interaction profiles, safety profiles, and efficacy.

Clinical Use

Famciclovir is indicated for the treatment of acute herpes zoster (shingles); it is at least as effective in reducing pain and healing time. Famciclovir is generally as effective as acyclovir in the treatment of HSV. In immunocompetent patients, famciclovir is approved for the treatment and prophylaxis of recurrent genital herpes. For HIV-infected individuals, famciclovir is approved for the treatment of all recurrent mucocutaneous HSV infections.

Clinical Use

Famciclovir is utilized in the treatment and suppression of herpes simplex infections, as well as in the treatment of zoster (secondary, dermatomal infection with VZV). In addition to these FDA-approved indications, it has also shown very limited activity in the treatment of HBV infections, but it is not recommended for this indication.

Side effects

Famciclovir may interact with probenecid or other drugs eliminated by renal tubular secretion. This interaction may result in increased blood levels of penciclovir or other agents.

Veterinary Drugs and Treatments

Famciclovir may be of benefit in treating feline herpes infections.

Drug interactions

Potentially hazardous interactions with other drugs
Probenecid: decreased excretion of famciclovir.
Increased famciclovir levels reported with mycophenolate mofetil.

Metabolism

Famciclovir is a pro-drug; it is rapidly converted to penciclovir; virtually no famciclovir is detectable in the plasma or urine. Bioavailability of penciclovir is reported to be 77%.
Famciclovir is mainly excreted in the urine (partly by renal tubular secretion) as penciclovir and its 6-deoxy precursor. No unchanged famciclovir has been detected in urine.

References

[1] hodge r a v, sutton d, boyd m r, et al. selection of an oral prodrug (brl 42810; famciclovir) for the antiherpesvirus agent brl 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl) guanine; penciclovir]. antimicrobial agents and chemotherapy, 1989, 33(10): 1765-1773.
[2] sáez-llorens x, yogev r, arguedas a, et al. pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection. antimicrobial agents and chemotherapy, 2009, 53(5): 1912-1920.