acyclovir except for an additional hydroxymethyl group on the side chain. Valganciclovir is the l-valyl ester prodrug of ganciclovir.
This agent has inhibitory activity against all herpesviruses but is especially active against CMV. Inhibitory concentrations for human bone marrow progenitors are similar to those inhibitory for CMV replication, a finding consistent with ganciclovir's myelotoxicity in clinical use.
mechanisms of action and resistance Ganciclovir inhibits viral DNA synthesis. It is monophosphorylated intracellularly by viral TK during HSV infection and by a viral phosphotransferase encoded by the UL97 gene during CMV infection. Ganciclovir diphosphate and ganciclovir triphosphate are formed by cellular enzymes. At least tenfold higher concentrations of ganciclovir triphosphate are present in CMV-infected than in uninfected cells. The triphosphate competitively inhibits deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral rather than host cellular DNA polymerases. Ganciclovir is incorporated into both viral and cellular DNA. Incorporation into viral DNA causes eventual cessation of DNA chain elongation (Figures 49-1Aand 49-2).
Intracellular ganciclovir triphosphate concentrations are tenfold higher than those of acyclovir triphosphate and decline much more slowly with an intracellular elimination t1/2 >24 hours. These differences may account for ganciclovir's greater anti-CMV activity and provide the rationale for single daily doses in suppressing human CMV infections.
CMV can become resistant to ganciclovir by reduced intracellular ganciclovir phosphorylation owing to mutations in the viral phosphotransferase encoded by the UL97 gene or mutations in viral DNA polymerase. Resistance has been associated primarily with impaired phosphorylation but sometimes only with DNA polymerase mutations. Highly resistant variants with dual UL97 and polymerase mutations are cross-resistant to cidofovir and variably to foscarnet. Ganciclovir also is much less active against acyclovir-resistant TK-deficient HSV strains.
ABSORPTION, DISTRIBUTION, AND ELIMINATION
The oral bioavailability of ganciclovir is ~6—9% following ingestion with food. Oral valganciclovir is well absorbed and hydrolyzed rapidly to ganciclovir; the bioavailability of ganciclovir is ~60%o following valganciclovir. Food increases the bioavailability of valganciclovir by ~25%. High oral valganciclovir doses with food provide ganciclovir exposures comparable with intravenous dosing. Following intravenous dosing, vitreous fluid levels equal or exceed those in plasma. Vitreous levels decline with a t/2 of 24 hours.
The plasma t/2 is ~2-4 hours in patients with normal renal function. Over 90% of ganciclovir is eliminated unchanged by renal excretion. Consequently, the plasma t/2 increases almost linearly as creatinine clearance declines and may reach 28-40 hours with severe renal insufficiency.
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