Antiherpesvirus Agents: Ganciclovir and Valganciclovir

Ganciclovir and Valganciclovir

Ganciclovir (Cytovene) is an acyclic analogue of 2 de-oxyguanosine with inhibitory activity toward all her-pesviruses, especially CMV. Valganciclovir (Valcyte) is the L-valyl ester prodrug of ganciclovir. Activation of ganciclovir first requires conversion to ganciclovir monophosphate by viral enzymes: protein kinase pUL97 in CMV or thymidine kinase in HSV. Host cell enzymes then perform two additional phosphorylations. The resultant ganciclovir triphosphate competes with dGTP for access to viral DNA polymerase. Its incorpo-ration into the growing DNA strand causes chain ter-mination in a manner similar to that of acyclovir. Ganciclovir triphosphate is up to 100-fold more concen-trated in CMV-infected cells than in normal cells and is preferentially incorporated into DNA by viral poly-merase. However, mammalian bone marrow cells are sensitive to growth inhibition by ganciclovir.

Resistance to ganciclovir has been found in individ-uals exposed to the drug for long periods and in people who have never been treated with this agent. The prin-cipal mechanism of resistance is mutation of the protein kinase gene. Mutations in the DNA polymerase have been seen more rarely.

Absorption, Metabolism, and Excretion

Ganciclovir can be given orally or intravenously; how-ever, its oral absorption is poor (6–9%). Valganciclovir is well absorbed from the gastrointestinal tract and is rapidly metabolized to ganciclovir. The bioavailability of ganciclovir following valganciclovir administration is approximately 60%. Following intravenous administra-tion, ganciclovir is found in the vitreous humor at concentrations approximately equal to plasma levels. Ganciclovir is not metabolized appreciably and is elim-inated by glomerular filtration and active tubular secre-tion. Its rate of elimination is inversely proportional to creatinine clearance. The terminal half-life of ganci-clovir is approximately 3.5 hours following intravenous administration and 4.8 hours following oral administra-tion. The half-life of ganciclovir following oral valganci-clovir administration is about 4 hours. The intracellular half-life of ganciclovir triphosphate is over 24 hours.

Clinical Uses

Intravenous ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised individuals, including those with AIDS, and for the prevention of CMV infection in organ transplant recipients. Oral gan-ciclovir is less effective than the intravenous prepara-tion but carries a lower risk of adverse effects. It is approved for the prevention of CMV disease in im-munocompromised individuals and transplant patients. It is also indicated as a maintenance therapy for treat-ment of CMV retinitis in AIDS and other immunocom-promised conditions. Ganciclovir is also available as an intravitreal implant (Vitrasert) for the treatment of CMV retinitis in AIDS patients.

Oral valganciclovir is comparable to intravenous ganciclovir for the treatment and suppression of CMV retinitis in AIDS patients.

Adverse Effects, Contraindications, and Drug Interactions

Myelosuppression is the most common serious adverse effect of ganciclovir treatment; therefore, patients’ blood counts should be closely monitored. Neutropenia and anemia have been reported in 25 to 30% of pa-tients, and thrombocytopenia has been seen in 5 to 10%. Elevated serum creatinine may occur following ganciclovir treatment, and dosage adjustment is re-quired for patients with renal impairment. In animal studies, ganciclovir causes decreased sperm production, teratogenesis, and tumor formation.

Ganciclovir interacts with a number of medications, some of which are used to treat HIV or transplant pa-tients. Ganciclovir may cause severe neutropenia when used in combination with zidovudine. Ganciclovir in-creases serum levels of didanosine, whereas probenecid decreases ganciclovir elimination. Nephrotoxicity may result if other nephrotoxic agents (e.g., amphotericin B, cyclosporine, NSAIDs) are administered in conjunction with ganciclovir.