Foscarnet (1998)

Foscarnet (trisodium phosphonoformate)is an antiviral agent that has activity against herpesviruses,including cytomegalovirus (CMV),Epstein-Barr virus, herpes simplex virus (HSV) types 1 and 2, and varicella zoster virus (VZV). It also has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).This analogue of the pyrophosphate released from deoxynucleoside triphosphates by the DNA polymerases during DNA synthesis acts by reversibly inhibiting the viral polymerases. Deoxynucleoside triphosphates and the DNA templates do not compete with foscarnet for binding to polymerases. Therefore,although intracellular deoxynucleotide triphosphate concentrations can affect the inhibitory action of nucleoside analogue antiviral agents like acyclovir and ganciclovir, they do not affect the action of foscarnet. Although the nucleoside analogue antiviral agents must be phosphorylated to their triphosphate form to function, foscarnet cannot be phosphorylated. Viral enzymes, such as thymidine kinase, phosphorylate the nucleoside analogue antivirals such as acyclovir and ganciclovir, making viruses that have mutant thymidine kinases relatively resistant to these agents. Because foscarnet does not require phosphorylation, mutations in thymidine kinase do not confer resistance to it. Viral polymerases can, however, develop specific resistance to foscarnet. Multiply resistant viruses also exist; a mutation in the HSV DNA polymerase has been described that produces a virus resistant to both foscarnet and ganciclovir.In vitro, foscarnet has an IC50(the concentration required to inhibit 50% of the enzyme activity) for the herpesvirus DNA polymerase ranging from 0.3 mcM (CMV) to 3.5 mcM (HSV-1, with some HIV-2 enzymes higher). The IC50 for the HIV reverse transcriptase is 0.1 to 0.5 mcM and for the hepatitis B DNA polymerase is 10 to 100 mcM. Although IC50 concentrations for viral replication (here, the concentration required to inhibit viral replication by 50%) depend on the assay system employed, IC50s for viral replication range from 50 to 800 mcM for CMV to 10 to 130 mcM for HSV 1 and 2 and 48 to 90 mcM for VZV. Other herpesviruses fall in those general ranges. The maximum plasma concentrations in patients receiving typical induction doses every 8 hours range from about 200 mcM to more than 1,000 mcM, with mean minimum plasma concentrations of 80 to 100 mcM.Foscarnet is used primarily to treat herpesvirus infections resistant to other antiviral agents in immunocompromised patients, especially those who have acquired immunodeficiency syndrome (AIDS). The most common indication is CMV retinitis, a frequent opportunistic infection in severely immunocompromised HIV patients whose CD4+cell counts are less than 50/mcL. Foscarnet has been used to treat CMV gastroenteritis, chronic mucocutaneous HSV infections, and chronic VZV infections due to acyclovir-resistant virus. Bone marrow transplantation patients who have CMV infections and patients who have fulminant hepatitis B infection also have been treated with foscarnet.Foscarnet-resistant virus can be produced in vitro, and clinical isolates resistant to foscarnet have been obtained. Such isolates have been associated with a poor clinical response, but herpesvirus isolates resistant to foscarnet may remain sensitive to other antivirals. In some patients whose severe disease is unresponsive to therapy with single agents, foscarnet in combination with ganciclovir has resulted in clinical response. In vitro, foscarnet and ganciclovir are synergistic. Some clinical evidence also suggests that foscarnet and other antiviral agents,including ganciclovir, may be synergistic;combination therapy with foscarnet and ganciclovir may be effective for CMV retinitis among AIDS patients refractory to other therapy.Studies comparing foscarnet with ganciclovir in AIDS patients who have CMV retinitis have shown that while foscarnet and ganciclovir have equivalent effects on retinitis, foscarnet treatment is associated with a modestly increased survival, probably due to its intrinsic antiretroviral effect. Even in AIDS patients, many physicians initially use ganciclovir rather than foscarnet because ganciclovir is better tolerated, has fewer toxicities, and is easier to administer. Foscarnet is the drug of choice for patients who have serious CMV or HSV infections and are known to be intolerant to ganciclovir or acyclovir or for patients known to be or suspected of being infected with a resistant virus.Foscarnet is administered intravenously. Oral bioavailability is limited,and oral administration is associated with diarrhea. Foscarnet has poor solubility in water and has a low pKa, limiting its ability to penetrate cells. Large doses are required to produce an in vivo antiviral effect, and these doses must be administered in large fluid volumes. It must be diluted prior to infusion into a peripheral intravenous line.Foscarnet undergoes minimal metabolism and is largely eliminated by the kidneys. About 90%of an intravenous dose is excreted unchanged in the urine. Following an intravenous dose, foscarnet is eliminated from serum with kinetics that vary among patients and dosing regimens. Foscarnet elimination has been described by using a three-compartment model, with an initial rapid decline that probably represents redistribution to soft tissues and a second phase that represents renal elimination. Most of an intravenous dose is eliminated with a half-life of 3 to 8 hours. Diminished renal function increases the half-life. Approximately 10% to 28% of a foscarnet dose enters bone and is eliminated with much longer kinetics. The cerebrospinal fluid concentration ranges between 31% and 69% of the steady-state plasma concentration.The recommended induction dose of foscarnet for CMV retinitis is 60 mg/kg every 8 hours for 2 to 3 weeks, followed by maintenance therapy at 90 to 120 mg/kg per day. The 120-mg dose is not clearly superior to the 90-mg dose. Many clinicians begin dosing at 90 mg,reserving the 120-mg dose for use following early relapse and reinduction. For acyclovir-resistant HSV,the recommended dose is 40 mg/kg every 8 to 12 hours. The rate of infusion must be controlled carefully because toxicities may be associated with transiently elevated plasma levels. Patients must be well hydrated,renal function should be carefully monitored, and the dose should be adjusted for compromised renal function.Foscarnet has several potential serious side effects, the most common of which is nephrotoxicity. As many as 60% of patients receiving foscarnet may develop up to two- to threefold elevations in serum creatinine. Some patients develop renal failure requiring hemodialysis,although the nephrotoxicity is generally reversible. Normal saline loading prior to foscarnet administration decreases renal toxicity, as does intermittent dosing. Other nephrotoxic agents can potentiate the nephrotoxic effects of foscarnet. Foscarnet can chelate divalent cations and has been associated with severe, occasionally fatal electrolyte disturbances, notably hypocalcemia,but also hypercalcemia, hypo- and hyperphosphatemia, hypokalemia,and hypomagnesemia. Intravenous pentamidine may potentiate hypocalcemia and should be avoided in patients receiving foscarnet. Electrolyte levels should be monitored carefully during therapy. Ionized calcium levels should be monitored in patients who have findings suggestive of hypocalcemia. Patients receiving foscarnet may develop anemia. Granulocytopenia has been seen, but unlike with ganciclovir, the granulocytopenia rarely reaches a level that requires stopping therapy. There are suggestions that patients receiving foscarnet may experience more seizures than comparable patients not receiving foscarnet. Some patients experience penile or vulvovaginal ulcerations, perhaps due to direct exposure to the high urine concentrations of foscarnet. About 20% to 30% of patients develop gastrointestinal side effects,including nausea and vomiting. Other less specific side effects occur at lower frequencies. The drug is potentially difficult and dangerous to use; the prescribing information should be reviewed carefully prior to initiating therapy.Although foscarnet does have significant side effects and toxicities and can be difficult to administer,its ability to treat potentially sight-and life-threatening CMV and HSV infections resistant to other available agents or patients intolerant to other agents make it a valuable antiviral therapeutic option.(The views expressed in this article are the author’s own and should not be considered the official opinions of the National Cancer Institute, the National Institutes of Health, or the United States Government.)