Foscarnet: An overview

INTRODUCTION — Foscarnet is principally used for the treatment of ganciclovir-resistant cytomegalovirus (CMV) infections in patients with the acquired immunodeficiency syndrome (AIDS) or in transplant recipients.

The mechanisms of action, pharmacokinetics, and adverse effects will be reviewed here. Treatment of the specific clinical syndromes can be found on the appropriate topic reviews.

MECHANISM OF ACTION — Foscarnet (trisodium phosphonoformate) is a pyrophosphate analog. It binds reversibly near the pyrophosphate-binding site of DNA polymerase (or reverse transcriptase) without requiring further modification [1]. After binding, the drug blocks the cleavage of the pyrophosphate moiety from deoxynucleotide triphosphates, in turn halting DNA chain elongation. Foscarnet selectively inhibits viral polymerase; inhibition of mammalian DNA polymerase requires a 100-fold greater concentration of foscarnet than that required to block cytomegalovirus (CMV) replication [1].

SPECTRUM OF ACTIVITY — Foscarnet inhibits the replication, at least in vitro, of multiple herpes family viruses, hepatitis B virus, and the human immunodeficiency virus (HIV) [1].

Clinically, foscarnet is employed almost exclusively to treat infections with cytomegalovirus (CMV; particularly when ganciclovir cannot be used) [2] and acyclovir-resistant herpes simplex virus (HSV) and varicella zoster virus (VZV). In selected cases, such as CMV encephalitis, foscarnet may be used in combination with ganciclovir. (See "AIDS-related cytomegalovirus neurologic disease".)

Foscarnet has in vitro activity against human herpesvirus 6A and 6B, and has been used in a few cases [3]. Foscarnet is not used as an antiretroviral agent to treat HIV.

ANTIVIRAL RESISTANCE — Resistance testing can identify mutations that help predict the activity of foscarnet [4-6]. This can be used to guide antiviral therapy, especially in patients who have failed their initial regimen.

●Foscarnet resistance can result from mutations in the CMV UL54 gene, which encodes the DNA polymerase that is important for viral replication. Mutations in this gene reduce antiviral affinity. UL54 mutations can emerge during therapy with foscarnet, and can also emerge in the presence of prolonged ganciclovir exposure, after the development of UL97 mutations (which confers resistance to ganciclovir but not to foscarnet).

●Although foscarnet is not used as an anti-HIV agent, mutations in the HIV reverse transcriptase gene may result in HIV resistance to foscarnet [7].

Foscarnet resistance is not seen in the presence of UL97 phosphotransferase mutations (seen in cytomegalovirus) or thymidine kinase mutations (seen in herpes simplex virus or varicella-zoster virus) since foscarnet does not require intracellular phosphorylation for antiviral activity. This is in contrast to the mechanism of resistance seen with acyclovir and ganciclovir. (See "Acyclovir: An overview" and "Ganciclovir and valganciclovir: An overview".)

BASIC PHARMACOKINETICS — Foscarnet has poor oral bioavailability and is therefore administered intravenously. Serum levels following a given dose can vary considerably, perhaps owing to differing equilibria resulting from foscarnet deposition in bone and cartilage [1]. Foscarnet is not significantly metabolized and is excreted solely by the kidneys, mainly via glomerular filtration and tubular secretion; bone and cartilage uptake accounts for roughly 20 percent of administered drug [1].

Peak concentrations with a regimen of 60 mg/kg thrice daily or 90 mg/kg twice daily range from about 400 to 700 micromol/L [1]. Elimination follows a three-phase pattern, with half-lives of about 1 h, 3 to 7 h, and 88 h [1].

Clearance decreases with impaired renal function, and dose adjustment in patients with renal insufficiency is required. Foscarnet is cleared by hemodialysis; concentrations in patients receiving 50 mg/kg after dialysis were similar to those in patients with normal renal function receiving 90 mg/kg twice daily [1]. A small study found vitreous concentrations roughly comparable to concomitant plasma levels [8].

TOXICITY — Specific toxicities are somewhat difficult to measure, given that foscarnet is used almost exclusively in patients with significant underlying illness who are often taking multiple medications. The most important adverse effects of foscarnet are decreased renal function, electrolyte abnormalities, and infusion-related nausea. Monitoring of renal function and electrolytes is important while on foscarnet therapy.

Renal insufficiency — According to the drug's manufacturer in a 1993 tabulation, 27 percent of 188 patients with AIDS receiving foscarnet in clinical trials experienced decreased renal function [1,9]. This impairment is usually reversible in persons with previously normal renal function [1].

Foscarnet appears to be directly toxic to the renal tubular cells [10]. Although tubular damage is probably the principal factor underlying foscarnet-induced renal dysfunction, the finding of crystals in the glomerular capillaries of three patients suggests that other mechanisms may contribute [11,12]. In one case report, a patient developed crystal nephropathy and multiorgan failure after the use of foscarnet [13].

The plasma creatinine concentration usually begins to rise after 6 to 15 days, the urinalysis is relatively bland, and biopsy tissue from a few patients has revealed acute tubular necrosis [14,15]. The primary tubular injury can also explain the frequent polyuria and polydipsia via interference with the action of antidiuretic hormone [16]; in some cases, arginine vasopressin resistance (AVP-R; previously called nephrogenic diabetes insipidus) has occurred in the absence of an elevation in the plasma creatinine concentration [17].

Renal toxicity appears to be reduced by concomitant saline (generally 0.5 to 1 L) administration. Administration of other nephrotoxic drugs such as amphotericin B or vancomycin along with foscarnet may increase the risk of renal insufficiency substantially [18-20].

Electrolyte abnormalities — Hypocalcemia is a well-established effect of foscarnet, possibly via complex formation between the drug and free calcium [21]. Hypomagnesemia is also commonly found and may contribute to the development of both hypocalcemia and hypokalemia [1,21] (see "Hypomagnesemia: Clinical manifestations of magnesium depletion"). Other electrolyte disturbances that may occur include hypophosphatemia, hypercalcemia, and hyperphosphatemia [1].

Seizures — Seizures have been associated with foscarnet in AIDS clinical trials, but it is unclear whether this effect reflects direct toxicity, drug-induced hypocalcemia, or underlying conditions [1].

Genital ulcerations — Genital ulcerations have been linked to foscarnet therapy, and it is suspected that a topical toxic effect of the drug concentrated in urine is responsible [1]. These lesions are reversible and potentially preventable with careful urinary hygiene.

Anemia — Anemia has been reported commonly in patients with AIDS receiving foscarnet, but, again, it is difficult to discern the degree of drug effect. Neutropenia, in contrast to the experience with ganciclovir, is uncommon with foscarnet therapy [1].

Nausea — Infusion-related nausea afflicts about a quarter of persons receiving foscarnet [1]. This problem, combined with the requirement for concomitant hydration and need for electrolyte monitoring, make this drug more difficult to administer than ganciclovir.

USE IN PREGNANCY AND DURING BREASTFEEDING — There are no adequate studies of the safety of foscarnet in pregnant women, and animal studies have suggested a risk of fetal skeletal abnormalities. In addition, it is not known whether foscarnet is secreted in human milk, although in lactating rats, the concentration in milk is higher than in blood. Thus, foscarnet should only be used in pregnant or breastfeeding patients if the anticipated benefits clearly exceed the potential risks [22].

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Foscarnet is a pyrophosphate analog that inhibits viral replication by selectively binding to viral DNA polymerase. (See 'Mechanism of action' above.)

●Spectrum of activity – In vitro, foscarnet inhibits the replication of multiple herpes family viruses, hepatitis B virus, and HIV. Clinically, foscarnet is used almost exclusively to treat patients with cytomegalovirus (CMV) infections, particularly when ganciclovir cannot be used, and acyclovir-resistant herpes simplex virus (HSV) and varicella zoster virus (VZV). (See 'Spectrum of activity' above.)

●Antiviral resistance – Unlike acyclovir or ganciclovir, foscarnet does not require intracellular phosphorylation for antiviral activity; thus, thymidine kinase mutations in HSV or VZV and UL97 phosphotransferase mutations in CMV do not confer drug resistance to foscarnet. (See 'Antiviral resistance' above.)

●Basic pharmacokinetics – Foscarnet has poor oral bioavailability and is therefore administered intravenously. Clearance decreases with impaired renal function; dose adjustment of foscarnet is required. (See 'Basic pharmacokinetics' above.)

●Toxicity – The most important adverse effects of foscarnet are decreased renal function, electrolyte abnormalities, and infusion-related nausea. (See 'Toxicity' above.)

•Renal insufficiency – The development of renal insufficiency on foscarnet is common among AIDS patients taking foscarnet, although renal impairment is usually reversible among patients with previously normal renal function. (See 'Renal insufficiency' above.)

•Electrolyte abnormalities – Hypocalcemia is a well-established effect of foscarnet, possibly via complex formation between the drug and free calcium. Hypomagnesemia is also common and may contribute to the development of both hypocalcemia and hypokalemia. (See 'Electrolyte abnormalities' above.)

●Pregnancy and lactation – There are no adequate studies of the safety of foscarnet in pregnant women, and animal studies have suggested a risk of fetal skeletal abnormalities. In addition, it is not known whether foscarnet is secreted in human milk. Thus, foscarnet should only be used in pregnant or breastfeeding patients if the anticipated benefits clearly exceed the potential risks. (See 'Use in pregnancy and during breastfeeding' above.)