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.
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.
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.
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.