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Valganciclovir: A New Oral Treatment for Cytomegalovirus Infection

Background: Cytomegalovirus (CMV) is latent in a large proportion of the normal population. This opportunistic agent causes clinical infection in patients with acquired immunodeficiency syndrome (AIDS) and in patients iatrogenically immunosuppressed after organ or bone marrow transplantation. In AIDS patients, CMV retinitis is the most common manifestation of infection and often leads to blindness. Intravenous (IV) ganciclovir is effective for acute treatment of CMV retinitis, and an oral formulation is used for long-term suppression. IV treatment is inconvenient and can be complicated by line infection. The efficacy of oral regimens is limited by poor absorption, even with thrice-daily dosing, and the large pill burden required may make adherence difficult. The new oral agent valganciclovir allows clinicians to circumvent these concerns.

Spectrum of Action: Valganciclovir (Valcyte^TM, Roche Laboratories, Nutley, New Jersey, USA) is approved for treatment of CMV retinitis in patients with AIDS. It is intended for once-daily dosing.

Pharmacology and Dosing: Valganciclovir (VGCV) is a prodrug valyl derivative of ganciclovir (GCV). After absorption through the gut, the valine moiety is rapidly cleaved off by the liver, yielding GCV. This compound, like acyclovir, is inactive and requires triphosphorylation for virostatic activity. The first phosphate can be attached only by a thymidine kinase coded for by the virus; the additional 2 phosphates are attached by cellular enzymes. The active drug is a guanosine analogue that inhibits viral (and cellular) DNA synthesis by chain termination.

VGCV is supplied as 450-mg tablets. The recommended induction dosage is 2 tablets taken twice daily with food for 21 days; food increases bioavailability. The maintenance dosage is 2 tablets taken once daily with food. In liver-transplant patients and in patients with AIDS, this dosage gives maximum serum concentrations and 24-hour total drug exposure equivalent to 5 mg/kg IV GCV twice daily and far greater concentrations than those achieved by the daily oral dosage of GCV. VGCV tablets should therefore not be substituted one-for-one with GCV capsules. Because VGCV is excreted primarily through the kidneys, dosage must be decreased in patients with impaired renal function.

Clinical Trials: In an open-label trial of induction therapy in 160 patients with newly diagnosed CMV retinitis, oral VGCV was as effective as comparable doses of IV GCV in stopping disease progression. No trials of maintenance therapy have been conducted.

Drug Resistance: Viruses resistant to GCV because of mutations in the CMV thymidine kinase or polymerase genes can be selected after prolonged treatment with VGCV. Initial resistance has also been noted in patients previously untreated with GCV.

Drug Interactions: VGCV and zidovudine, a staple of AIDS therapy, both have the potential to suppress bone marrow function. Probenecid may elevate GCV levels, leading to toxicity. VGCV may increase the toxicity of other renally excreted drugs, such as didanosine and zidovudine and metabolites of mycophenolate mofetil (an immunosuppressant).

Contraindications and Side Effects: VGCV should not be given to patients on hemodialysis because the smallest available dose may be too high. As with GCV, the most serious adverse effect is suppression of bone marrow elements; therefore, VGCV should not be given to patients in whom the total neutrophil count is < 500/uL, the platelet count is < 25,000/uL, or hemoglobin is < 8g/dL. Other adverse effects, similar to those seen with GCV, include gastrointestinal upset, fever, headache, and insomnia. VGCV is teratogenic and decreases spermatogenesis in animals. Effective contraception should therefore be used during treatment. Breast-feeding while on VGCV is contraindicated. There are no studies of VGCV in children or patients older than 65.

Comment: This drug was successfully developed to increase the oral bioavailability of GCV. Although there are no studies of maintenance therapy and no studies of efficacy in systemic CMV infection in transplant patients and other immunosuppressed patients, valganciclovir will likely be as effective as IV ganciclovir for these conditions. Although valganciclovir is more expensive per pill than ganciclovir, the added costs of administration with IV ganciclovir and the lower per-dose pill count with oral valganciclovir compared with oral ganciclovir mean that costs are comparable. CMV prophylaxis in AIDS patients is controversial and is not recommended.

-- S Baum

References

Hoffman La Roche, Inc. Valcyte^TM product information.

Gilbert DN, Moellering RC Jr., Sande MA, eds. Sanford Guide to Antimicrobial Therapy. 21st ed. Vienna, VA: Antimicrobial Therapy, Inc.; 2001:105.

Published in Journal Watch Infectious Diseases July 27, 2001

Citation(s):

Brown F et al. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 1999 Aug 37 167-176.

• Medline abstract (Free)

Reusser P. Antiviral therapy: Current options and challenges. Schweiz Med Wochenschr 2000 130 101-112.

• Medline abstract (Free)

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