Antiherpesvirus Agents: Cidofovir

Cidofovir

Cidofovir (Vistide) is an acyclic phosphonate cytosine analogue with activity against herpesviruses including CMV, HSV-1, HSV-2, EBV, and VZV. It also inhibits adenoviruses, papillomaviruses, polyomaviruses, and poxviruses. Activation of cidofovir requires metabolism to a diphosphate by host cellular enzymes. Because this activation does not depend upon viral enzymes, similar levels of cidofovir diphosphate are seen in infected and uninfected cells. Cidofovir diphosphate competes with deoxycytidine triphosphate (dCTP) for access to viral DNA polymerase and also acts as an alternative sub-strate. The incorporation of one cidofovir molecule into the growing DNA chain slows replication; sequential in-corporation of two molecules halts DNA polymerase activity.

Absorption, Metabolism, and Excretion

Cidofovir has extremely low oral bioavailability and so must be administered intravenously. Although the plasma elimination half-life averages 2.6 hours, the diphosphate form of the drug is retained within host cells and has an intracellular half life of 17 to 65 hours. A phosphocholine metabolite has a half-life of approx-imately 87 hours and may serve as an intracellular reservoir of the drug. Cidofovir is not significantly me-tabolized and is excreted unchanged by the kidney. Glomerular filtration and probenecid-sensitive tubular secretion are responsible for cidofovir elimination.

Clinical Uses

Cidofovir is approved for the treatment and prophy-laxis of CMV retinitis in AIDS patients. It has also been used in the treatment of acyclovir-resistant (viral thymi-dine kinase-deficient) HSV infections, polyomavirus-associated progressive multifocal leukoencephalopathy, condylomata acuminata (anogenital warts), and mollus-cum contagiosum.

Adverse Effects, Contraindications, and Drug Interactions

The most immediately serious adverse effect associated with cidofovir therapy is nephrotoxicity. Accumulation of the drug within the proximal tubule epithelial cells can lead to proteinuria, azotemia, glycosuria, elevated serum creatinine, and rarely, Fanconi’s syndrome. Probenecid is administered along with cidofovir to block its uptake into the proximal tubule epithelial cells and thereby inhibit its tubular secretion as well as its toxicity. Probenecid carries its own adverse effects, in-cluding gastrointestinal upset, hypersensitivity reac-tions, and a decrease in the elimination of drugs that also undergo active tubular secretion (e.g. nonsteroidal antiinflammatory drugs [NSAIDs], penicillin, acyclovir, zidovudine).

Anterior uveitis and neutropenia are fairly common side effects of cidofovir therapy. Ocular hypotony and metabolic acidosis are rare. Exposure to therapeutic levels of cidofovir causes cancer in rats; therefore, this drug should be considered a potential human carcino-gen. Animal studies have also shown cidofovir to pro-duce embryotoxic and teratogenic effects and to impair fertility.

Because of its potential nephrotoxicity, cidofovir should not be used in individuals with renal impairment. Nephrotoxic agents (e.g., aminoglycosides, NSAIDs, amphotericin B, foscarnet) should not be given within 7 days of cidofovir administration.