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Chapter: Modern Pharmacology with Clinical Applications: Antiviral Drugs

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Antiherpesvirus Agents: Famciclovir and Penciclovir

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

Famciclovir and Penciclovir

 

Famciclovir (Famvir) is the diacetyl ester prodrug of the acyclic guanosine analogue 6-deoxypenciclovir (Dena-vir). Penciclovir has activity against HSV-1, HSV-2, VZV, and HBV. After oral administration, famciclovir is converted to penciclovir by first-pass metabolism. Penciclovir has a mechanism of action similar to that of acyclovir. It is first monophosphorylated by viral thymi-dine kinase; then it is converted to a triphosphate by cellular kinases. Penciclovir triphosphate acts as a com-petitive inhibitor of viral DNA polymerase, but unlike acyclovir, it does not cause chain termination.

 

Mutations in DNA polymerase or thymidine kinase may result in resistance. Acyclovir-resistant HSV strains that exhibit thymidine kinase deficiency are also resistant to famciclovir and penciclovir.

 

Absorption, Metabolism, and Excretion

 

Penciclovir is available as a topical cream; its absorption through the skin is undetectable. Famciclovir is well absorbed following oral administration and is rapidly converted to penciclovir by hepatic first-pass metabo-lism. The bioavailability of penciclovir following oral famciclovir administration is approximately 77%. Penciclovir is less than 20% bound to plasma proteins.

 

The plasma elimination half-life for penciclovir is 2 to 3 hours; however, the intracellular half-life of penci-clovir triphosphate is 7 to 20 hours in infected cells. Most penciclovir is eliminated unchanged by the kidney via glomerular filtration and active tubular secretion. The plasma half-life is increased in individuals with re-nal insufficiency.

 

Clinical Uses

 

Penciclovir is approved as a topical formulation for the treatment of herpes labialis. In immunocompetent indi-viduals, penciclovir shortens the duration of lesion pres-ence and pain by approximately half a day when it is ini-tiated within an hour of lesion development and applied every 2 hours during waking hours for 4 days.

 

Famciclovir is indicated for the treatment of acute herpes zoster (shingles); it is at least as effective in re-ducing pain and healing time. Famciclovir is generally as effective as acyclovir in the treatment of HSV. In im-munocompetent patients, famciclovir is approved for the treatment and prophylaxis of recurrent genital her-pes. For HIV-infected individuals, famciclovir is ap-proved for the treatment of all recurrent mucocuta-neous HSV infections.

 

 

Adverse Effects, Contraindications, and Drug Interactions

 

No significant adverse effects to topical penciclovir have been reported. Oral famciclovir is generally well tolerated. Adverse effects include headache, nausea, and diarrhea. Confusion may occur, particularly in the elderly. Hallucinations and urticaria have been re-ported. Animal studies have indicated that chronic fam-ciclovir administration may be tumorigenic and impair spermatogenesis. Dosage adjustment is necessary in in-dividuals with renal impairment.

 

Famciclovir may interact with probenecid or other drugs eliminated by renal tubular secretion. This inter-action may result in increased blood levels of penci-clovir or other agents.

 

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