What is Foscarnet?

What is Foscarnet?

Foscarnet (trisodium phosphonoformate) is an intravenous antiviral agent that directly inhibits viral DNA polymerase and HIV reverse transcriptase without requiring intracellular activation, primarily used as an alternative treatment for cytomegalovirus (CMV) disease and ganciclovir-resistant CMV infections in immunocompromised patients. 1

Mechanism of Action

• Foscarnet is a pyrophosphate analogue that selectively inhibits viral DNA polymerase at the pyrophosphate binding site, preventing viral replication at concentrations that do not affect cellular DNA polymerases 1
• Unlike ganciclovir, foscarnet does not require phosphorylation by thymidine kinase or other kinases for antiviral activity, making it effective against acyclovir-resistant and ganciclovir-resistant viral strains 1, 2
• The drug inhibits all human herpesviruses including CMV (at concentrations of 100-300 μmol/L), HSV-1, HSV-2, and has dose-related inhibitory effects on HIV-1 2, 3

Clinical Indications

Primary Uses

• Alternative treatment for CMV disease (including retinitis, gastrointestinal disease, and encephalitis) in HIV-infected patients when ganciclovir is contraindicated or has failed 4
• Treatment of ganciclovir-resistant CMV infections 4
• Treatment of acyclovir-resistant herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections 2, 3

Specific Clinical Scenarios

• For CMV retinitis in AIDS patients, foscarnet achieves healing or stabilization in 85-95% of patients after 2-3 weeks of therapy 2, 5
• Foscarnet when used for CMV suppression has been associated with increased length of survival relative to ganciclovir in HIV-infected adult patients, likely due to its inherent anti-HIV activity and compatibility with zidovudine 4, 3
• For CMV encephalitis, combination therapy with ganciclovir (5 mg/kg IV q12h) and foscarnet (60 mg/kg IV q8h or 90 mg/kg IV q12h) for 3 weeks is recommended, with improvement or stabilization in 74% of HIV-infected patients 4

Dosing and Administration

Pediatric Dosing

• Induction: 60 mg/kg/dose IV every 8 hours over 1-2 hours for 14-21 days, followed by lifelong maintenance therapy 4
• The dose must be administered slowly over 2 hours (no faster than 1 mg/kg/minute) 4

Adult Dosing (from research evidence)

• Induction: 60 mg/kg IV three times daily or 90-100 mg/kg IV twice daily 2
• Maintenance: Daily administration required to prevent rapid relapse 2, 6

Critical Administration Requirements

• Infusing foscarnet with saline fluid loading can minimize renal toxicity 4
• Doses must be modified in patients with renal insufficiency 4

Pharmacokinetics

• Foscarnet is mainly eliminated unchanged by the kidneys with a mean half-life of 3.4-5 hours 2, 7
• Oral bioavailability is extremely low (12-22%), requiring intravenous administration 2
• Mean plasma clearance is 1.7-1.9 ml/min/kg, correlating directly with renal function 7
• Volume of distribution is approximately 0.74 L/kg 7
• Almost 90% of a foscarnet dose is excreted in urine 3

Major Toxicities and Adverse Effects

Renal Toxicity (Most Significant)

• The main toxicity is decreased renal function; up to 30% of patients experience increased serum creatinine levels due to acute tubular toxicity 4, 2
• Reversible renal insufficiency can occur but may be partially prevented by hyperhydration during treatment 2, 5

Electrolyte Disturbances

• Foscarnet binding to divalent metal ions (calcium, magnesium) leads to metabolic abnormalities in approximately one-third of patients 4
• Serious electrolyte imbalances include abnormalities in calcium, phosphorus, magnesium, and potassium levels, with secondary complications including seizures and cardiac dysrhythmias 4
• Fluctuations in serum calcium and phosphate levels occur frequently, with most clinical symptoms related to decreased ionized calcium 2
• Hyperphosphatemia is a clinically benign phenomenon reflecting foscarnet incorporation into bone 2

Other Adverse Effects

• CNS symptoms, abnormal liver transaminases, anemia, nausea and vomiting 4, 3
• Penile ulcerations have been described and may result from mucocutaneous direct toxicity of foscarnet eliminated in urine 2
• Phlebitis at infusion sites 6

Key Clinical Advantages

• Unlike ganciclovir, foscarnet does not cause myelosuppression (neutropenia, anemia, thrombocytopenia), making it particularly useful when combined with bone marrow toxic drugs such as zidovudine 5, 6
• The different tolerability profiles of foscarnet and zidovudine facilitate combination use in AIDS patients with CMV infection 3
• Foscarnet demonstrates activity against ganciclovir-resistant CMV strains 4, 1

Important Clinical Caveats

• CMV disease is not cured with foscarnet; after induction therapy, secondary prophylaxis (chronic maintenance therapy) is recommended for life unless immune reconstitution occurs with HAART 4
• Relapse occurs rapidly (within 3 weeks) after discontinuation of foscarnet without maintenance therapy 5, 6
• Viral resistance can develop through amino acid substitutions in viral DNA polymerase, and should be considered in patients with poor clinical response or persistent viral excretion 1
• Combination therapy with ganciclovir and foscarnet delays progression of retinitis in patients failing monotherapy and can be used as initial therapy for sight-threatening disease 4