Foscarnet Explained

Foscarnet (phosphonomethanoic acid), known by its brand name Foscavir, is an antiviral medication which is primarily used to treat viral infections involving the Herpesviridae family. It is classified as a pyrophosphate analog DNA polymerase inhibitor.^{[1] [2]} Foscarnet is the conjugate base of a chemical compound with the formula HO₂CPO₃H₂ (Trisodium phosphonoformate).^{[3] [4]}

Foscarnet was approved for medical use in 1991.^[5] It is available as a generic medication.^[6]

Medical use

This phosphonic acid derivative (marketed by Clinigen as foscarnet sodium under the trade name Foscavir) is an antiviral medication used to treat herpes viruses, including drug-resistant cytomegalovirus (CMV) and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2). It is particularly used to treat CMV retinitis. Foscarnet can be used to treat highly treatment-experienced patients with HIV as part of salvage therapy.^{[7] [8]}

Mechanism of action

Foscarnet is a structural mimic of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases.^[9]

In individuals treated with the DNA polymerase inhibitors acyclovir or ganciclovir, HSV or CMV particles can develop mutant protein kinases (thymidine kinase or UL97 protein kinase, respectively) that make them resistant to these antiviral drugs.^{[10] [11]} However, unlike acyclovir and ganciclovir, foscarnet is not activated by viral protein kinases, making it useful in acyclovir- or ganciclovir-resistant HSV and CMV infections.

However, acyclovir- or ganciclovir-resistant mutants with alterations in viral DNA polymerase may also be resistant to foscarnet.^{[12] [13]}

Administration

Foscarnet is administered by intravenous infusion or intravitreous injection.

Side effects

• Nephrotoxicity — increase in serum creatinine levels and renal injury can occur in patients receiving foscarnet.^[14] Other nephrotoxic drugs should be avoided. Nephrotoxicity is usually reversible and can be reduced by dosage adjustment and adequate hydration.^[15]
• Electrolyte disturbances — hypocalcemia and hypomagnesemia can occur^[16] and regular monitoring of electrolytes is necessary to avoid clinical toxicity.^[17]
• Genital ulceration — a less common reported side effect which occurs more in men and usually during induction use of foscarnet. It is most likely a contact dermatitis due to high concentrations of foscarnet in urine. It usually resolves rapidly following discontinuation of the drug.^[18]
• CNS — less common side effects of perioral paresthesia, irritability and altered mental states.

Sources

• Dennis L. Kasper, Eugene Braunwald. "Harrison's Manual of Medicine", 16th Edition, Mcgraw-hill, (2005), p. 2244.

External links

• Web site: Foscarnet . U.S. National Library of Medicine . Drug Information Portal .
• Web site: Foscarnet sodium . U.S. National Library of Medicine . Drug Information Portal .

Notes and References

1. Wagstaff AJ, Bryson HM . Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections . Drugs . 48 . 2 . 199–226 . August 1994 . 7527325 . 10.2165/00003495-199448020-00007 . 260483894 .
2. Chrisp P, Clissold SP . Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis . Drugs . 41 . 1 . 104–129 . January 1991 . 1706982 . 10.2165/00003495-199141010-00009 . free .
3. Book: Garikapati S, Nguyen M . Foscarnet . 2022 . http://www.ncbi.nlm.nih.gov/books/NBK556108/ . StatPearls . Treasure Island (FL) . StatPearls Publishing . 32310568 . 2022-04-04 .
4. Web site: phosphonoformic acid (CHEBI:127780) . 2022-04-04 . www.ebi.ac.uk.
5. Book: Long SS, Pickering LK, Prober CG . Principles and Practice of Pediatric Infectious Disease. 2012. Elsevier Health Sciences. 978-1437727029. 1502. en.
6. Web site: Competitive Generic Therapy Approvals . U.S. Food and Drug Administration (FDA) . 29 June 2023 . 29 June 2023 . 29 June 2023 . https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals . live .
7. Canestri A, Ghosn J, Wirden M, Marguet F, Ktorza N, Boubezari I, Dominguez S, Bossi P, Caumes E, Calvez V, Katlama C . 6 . Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistance . Antiviral Therapy . 11 . 5 . 561–566 . 2006 . 16964823 . 10.1177/135965350601100501 . 24905247 . free .
8. Mathiesen S, Dam E, Roge B, Joergensen LB, Laursen AL, Gerstoft J, Clavel F . Long-term foscarnet therapy remodels thymidine analogue mutations and alters resistance to zidovudine and lamivudine in HIV-1 . Antiviral Therapy . 12 . 3 . 335–343 . 2007 . 17591023 . 10.1177/135965350701200310 . 19856772 . free .
9. Meyer PR, Rutvisuttinunt W, Matsuura SE, So AG, Scott WA . Stable complexes formed by HIV-1 reverse transcriptase at distinct positions on the primer-template controlled by binding deoxynucleoside triphosphates or foscarnet . Journal of Molecular Biology . 369 . 1 . 41–54 . May 2007 . 17400246 . 1986715 . 10.1016/j.jmb.2007.03.006 .
10. Chou S . Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir . Reviews in Medical Virology . 18 . 4 . 233–246 . July 2008 . 18383425 . 10.1002/rmv.574 . 42775774 . free .
11. Frobert E, Ooka T, Cortay JC, Lina B, Thouvenot D, Morfin F . Herpes simplex virus thymidine kinase mutations associated with resistance to acyclovir: a site-directed mutagenesis study . Antimicrobial Agents and Chemotherapy . 49 . 3 . 1055–1059 . March 2005 . 15728902 . 549244 . 10.1128/aac.49.3.1055-1059.2005 .
12. Bonnafous P, Naesens L, Petrella S, Gautheret-Dejean A, Boutolleau D, Sougakoff W, Agut H . Different mutations in the HHV-6 DNA polymerase gene accounting for resistance to foscarnet . Antiviral Therapy . 12 . 6 . 877–888 . 2007 . 17926642 . 10.1177/135965350701200608 . 24584000 . free .
13. Tchesnokov EP, Gilbert C, Boivin G, Götte M . Role of helix P of the human cytomegalovirus DNA polymerase in resistance and hypersusceptibility to the antiviral drug foscarnet . Journal of Virology . 80 . 3 . 1440–1450 . February 2006 . 16415021 . 1346920 . 10.1128/JVI.80.3.1440-1450.2006 .
14. Ota R, Hirata A, Noto K, Yokoyama S, Hosomi K, Takada M, Matsuoka H . Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet . International Journal of Clinical Pharmacology and Therapeutics . 58 . 5 . 274–281 . May 2020 . 32101522 . 10.5414/CP203650 . 211537187 .
15. Jacobson MA . Review of the toxicities of foscarnet . Journal of Acquired Immune Deficiency Syndromes . 5 . Suppl 1 . S11–S17 . 1992-01-01 . 1534839 .
16. Gearhart MO, Sorg TB . Foscarnet-induced severe hypomagnesemia and other electrolyte disorders . The Annals of Pharmacotherapy . 27 . 3 . 285–289 . March 1993 . 8384030 . 10.1177/106002809302700304 . 37250222 .
17. Zareifopoulos N, Lagadinou M, Karela A, Kyriakopoulou O, Velissaris D . Neuropsychiatric Effects of Antiviral Drugs . Cureus . 12 . 8 . e9536 . August 2020 . 32905132 . 7465925 . 10.7759/cureus.9536 . free .
18. Adalsteinsson JA, Pan M, Kaushik S, Ungar J . Foscarnet-induced genital lesions: An overview with a case report . Dermatology Reports . 10 . 1 . 7749 . April 2018 . 29991980 . 6026811 . 10.4081/dr.2018.7749 .