Foscarnet

Foscarnet is an antiviral agent with a broad spectrum inhibiting all known human viruses of the herpes group: herpes simplex virus type 1 and 2; human herpes virus 6; varicella zoster virus; Epstein-Barr virus and cytomegalovirus (CMV) and some retroviruses, including human immunodeficiency virus (HIV) at concentrations not affecting normal cell growth. Foscarnet also inhibits the viral DNA polymerase from hepatitis B virus.

Foscarnet exerts its antiviral activity by a direct inhibition of viral specific DNA polymerase a reverse transcriptase at concentrations that do not affect cellular DNA polymerases. Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV mutants deficient in thymidine kinase.

CMV strains resistant to ganciclovir may be sensitive to foscarnet. Sensitivity test results expressed as concentration of the drug required to inhibit growth of virus by 50% in cell culture (IC₅₀) vary greatly depending on the assay method used and cell type employed. A number of sensitive viruses and their IC₅₀ are listed below.

Foscarnet inhibition of virus multiplication cell culture:

* Mean = 269 micrograms
** 97% of viral antigen synthesis inhibited at 500 micrograms

If no clinical response to foscarnet is observed, viral isolates should be tested for sensitivity to foscarnet since naturally resistant mutants may exist or emerge under selective pressure both in vitro and in vivo.

The mean foscarnet 50% inhibition value for more than one hundred clinical CMV isolates was approximately 270 micrograms/L, while a reversible inhibition of normal cell growth was observed at about 1000 micrograms/L.

There is no evidence of an increased myelotoxicity when foscarnet is used in combination with zidovudine (AZT).

Foscarnet is eliminated by the kidneys mainly through glomerular filtration. The plasma clearance after intravenous administration to man varies between 130–160 ml/min and the renal clearance is about 130 ml/min. The half-life is in the order of 2–4 hours in patients with normal renal function.

The mean volume of distribution of foscarnet at steady state varies between 0.4–0.6 L/kg. There is no metabolic conversion of foscarnet and the binding to human plasma proteins is low (<20%). Foscarnet is distributed to the cerebrospinal fluid and concentrations ranging from 10 to 70% of the concurrent plasma concentrations have been observed in HIV-infected patients.

The most pronounced effects noted during general toxicity studies performed with foscarnet are perturbation of some serum electrolytes, and kidney and bone changes.

An observed reduction of serum electrolytes such as calcium and magnesium can be explained by the property of foscarnet to form chelate with divalent metal ions. The reduction of ionised calcium and magnesium is, most probably the explanation to seizures/convulsions seen during and shortly after the infusion of high doses of foscarnet. This reduction may also have a bearing on heart function (e.g. ECG) although the toxicological studies performed did not disclose any such effects. The rate of infusion of foscarnet is critical to disturbances in the homeostasis of some serum divalent cations.

The mechanism behind the kidney changes e.g. tubular atrophy, mainly confined to juxtamedullary nephrons, is less clear. The changes were noted in all species investigated. It is known that other complex binders of divalent cations (EDTA and biphosphonates) can cause changes of the kidney similar to those of foscarnet. It has been shown that hydration, to induce diuresis, significantly reduces kidney changes during foscarnet treatment.

The bone changes were characterised as increased osteoclast activity and bone resorption. Roughly 20% of the administered drug is taken up into bone and cartilage and deposition is greater in young and growing animals. This effect has only been seen in the dog. The reason to these changes may be that foscarnet, due to the structural similarity to phosphate is incorporated into the hydroxyapatite. Autoradiographic studies showed that foscarnet has a pronounced affinity to bone tissue. Recovery studies revealed that the bone changes were reversible. Foscarnet sodium has been demonstrated to adversely affect development of tooth enamel in mice and rats. The effects of this deposition on skeletal development have not been studied.

Mutagenicity studies showed that foscarnet has a genotoxic potential. The possible explanation for the observed effect in the mutagenicity studies is an inhibition of the DNA polymerase in the cell line used. Foscarnet therapeutically acts by inhibition of the herpes virus specific DNA polymerase. The human cellular polymerase is about 100 times less sensitive to foscarnet. The carcinogenicity studies performed did not disclose any oncogenic potential. The information gained from teratogenicity and fertility studies did not reveal any adverse events upon the reproductive process. However, the results are of limited value since the dose levels used in these studies are below or at most similar (75–150 mg/kg sc) to those used in man for treatment of CMV retinitis.