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.
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.
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.
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.
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