Antiherpesvirus Agents: Foscarnet

Foscarnet

Foscarnet (Foscavir) is an inorganic pyrophosphate ana-logue that acts in vitro against HSV-1, HSV-2,VZV, CMV, EBV, HBV, and HIV. It acts as a noncompetitive inhibitor of viral DNA polymerase and reverse transcriptase by re-versibly binding to the pyrophosphate-binding site of the viral enzyme and preventing the cleavage of pyrophos-phate from deoxynucleoside triphosphates.

Resistance to foscarnet may result from mutation of viral DNA polymerase. Because this drug does not require phosphorylation for activation, thymidine kinase–deficient mutants should not be resistant to fos-carnet.

Absorption, Metabolism, and Excretion

Because of its poor oral bioavailability, foscarnet is ad-ministered intravenously. Following intravenous infu-sion, 14 to 17% of foscarnet is bound to plasma pro-teins. The concentration of this compound in the vitreous humor is approximately the same as its plasma level. Foscarnet accumulates in bone; this property may account for its bimodal initial half-life of 4 to 8 hours and prolonged terminal elimination half-life of 45 to 130 hours. Foscarnet is eliminated primarily as un-changed drug via glomerular filtration and active tubu-lar secretion.

Clinical Uses

Foscarnet is indicated for the treatment of CMV retini-tis in AIDS patients. Its effectiveness is comparable to that of ganciclovir; these drugs are synergistic when given to counteract refractory retinitis. A decreased in-cidence of Kaposi’s sarcoma has been observed in AIDS patients who have undergone foscarnet therapy.

Foscarnet is approved for the treatment of acyclovir-resistant mucocutaneous HSV infections in immuno-compromised individuals. A clinical study indicated that it is more effective than vidarabine. Foscarnet has also been used for the treatment of acyclovir-resistant VZV and nonretinitis forms of CMV infection, although its efficacy is not so well established.

Adverse Effects, Contraindications, and Drug Interactions

The most clinically significant adverse effect of foscarnet is renal impairment. Nephrotoxicity is most likely to oc-cur during the second week of induction therapy but may occur at any time during induction or maintenance ther-apy. Serum creatinine levels may be elevated in up to 33 to 50% of patients; this effect is usually reversible upon drug discontinuation. Dehydration, previous renal im-pairment, and concurrent administration of other nephrotoxic drugs increase the risk of renal toxicity. Infusion of fluids along with foscarnet decreases the like-lihood of renal impairment to about 12%. Dosage ad-justment is required for patients with renal insufficiency.

Foscarnet is also associated with adverse effects on a variety of other organ systems. It may induce changes in serum electrolytes, including hypocalcemia, hy-pophosphatemia, hyperphosphatemia, hypomagne-semia, and hypokalemia. Neurological and cardiovascu-lar signs such as paresthesia, tetany, arrhythmias, and seizures may result from these mineral imbalances. Anemia and granulocytopenia occur fairly commonly but seldom require discontinuation of therapy. Headache, vomiting, and diarrhea also occur with regu-larity. Genital ulceration has been reported and is likely due to high levels of ionized drug in the urine. While studies in rats indicate a lack of carcinogenicity, cell cul-ture studies suggest a mutagenic effect. The safety of foscarnet during childhood, pregnancy, and lactation has not been established.

Foscarnet should not be used in combination with drugs that cause renal toxicity (e.g., acyclovir, aminogly-cosides, amphotericin B, NSAIDs). Abnormal renal function has been noted when foscarnet is used with ri-tonavir or ritonavir and saquinavir. Pentamidine may increase the risk of nephrotoxicity, hypocalcemia, and hypomagnesemia. Caution should be used when foscar-net is given in combination with agents that can cause mineral imbalances.