Cidofovir

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Cidofovir
130px
200px
Systematic (IUPAC) name
({[(S)-1-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxypropan-2-yl]oxy}methyl)phosphonic acid
Clinical data
Trade names Vistide
AHFS/Drugs.com monograph
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 IV
Pharmacokinetic data
Bioavailability complete
Protein binding <6%
Biological half-life 2.6 hours (active metabolites: 15-65 hours)
Excretion renal The above pharmacokinetic parameters are measured for cidofovir used in conjunction with probenecid.[1]
Identifiers
CAS Number 113852-37-2 YesY
ATC code J05AB12 (WHO)
PubChem CID: 60613
DrugBank DB00369 YesY
ChemSpider 54636 YesY
UNII 768M1V522C YesY
ChEBI CHEBI:3696 YesY
ChEMBL CHEMBL152 YesY
NIAID ChemDB 001049
Chemical data
Formula C8H14N3O6P
Molecular mass 279.187 g/mol
  • O=C1/N=C(\C=C/N1C[C@H](OCP(=O)(O)O)CO)N
  • InChI=1S/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)/t6-/m0/s1 YesY
  • Key:VWFCHDSQECPREK-LURJTMIESA-N YesY
Physical data
Melting point 260 °C (500 °F)
Specific rotation -97.3
  (verify)

Cidofovir (brand name Vistide) is an injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis (an infection of the retina of the eye) in people with AIDS.[2][3]

Medical uses

DNA virus

Its only indication that has received regulatory approval worldwide is cytomegalovirus retinitis.[2][3] Cidofovir has also shown efficacy in the treatment of aciclovir-resistant HSV infections.[4] Cidofovir has also been investigated as a treatment for progressive multifocal leukoencephalopathy with successful case reports of its use.[5] Despite this, the drug failed to demonstrate any efficacy in controlled studies.[6] Cidofovir might have anti-smallpox efficacy and might be used on a limited basis in the event of a bioterror incident involving smallpox cases.[7] Brincidofovir, a cidofovir derivative with much higher activity against smallpox that can be taken orally has been developed.[8] It has inhibitory effects on varicella-zoster virus replication in vitro although no clinical trials have been done to date, likely due to the abundance of safer alternatives such as aciclovir.[9] Cidofovir shows anti-BK virus activity in a subgroup of transplant recipients.[10] Cidofovir is being investigated as a complementary intralesional therapy against papillomatosis caused by HPV.[11][12]

It first received FDA approval on the 26th of June 1996,[13] TGA approval on the 30th of April 1998[3] and EMA approval on the 23rd of April 1997.[14]

Other

It has been suggested as an antitumour agent, due to its suppression of FGF2.[15][16]

Administration

Cidofovir is only available as an intravenous formulation. Cidofovir is to be administered with probenecid to help mitigate harm and decrease side effects to the kidney.[17] Probenecid works to mitigate nephrotoxicity by inhibiting organic anion transport of the proximal tubule epithelial cells of the kidney.[18] In addition, hydration must be administered to patients receiving cidofovir. 1 liter of normal saline is recommended in conjunction with each dose of cidofovir.[17]

Side effects

The major dose-limiting side effect of cidofovir is nephrotoxicity (that is, kidney damage).[19] Other common side effects (occurring in >1% of people treated with the drug) include:[2][19]

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Whereas uncommon side effects include: anaemia and elevated liver enzymes and rare side effects include: tachycardia and Fanconi syndrome.[19] Probenecid (a uricosuric drug) and intravenous saline should always be administered with each cidofovir infusion to prevent this nephrotoxicity.[20]

Contraindications

Hypersensitivity to cidofovir or probenecid (as probenecid needs to be given concurrently to avoid nephrotoxicity).[2]

Interactions

It is known to interact with nephrotoxic agents (e.g. amphotericin B, foscarnet, IV aminoglycosides, IV pentamide, vancomycin, tacrolimus, non-steroid anti-inflammatory drugs, etc.) to increase their nephrotoxic potential.[2][3] As it must be given concurrently with probenecid it is advised that drugs that are known to interact with probenecid (e.g. drugs that probenecid interferes with the renal tubular secretion of, such as paracetamol, aciclovir, aminosalicylic acid, etc.) are also withheld.[3]

Mechanism of action

Its active metabolite, cidofovir diphosphate, inhibits viral replication by selectively inhibiting viral DNA polymerases.[3] It also inhibits human polymerases but this action is 8-600 times weaker than its actions on viral DNA polymerases.[3] It also incorporates itself into viral DNA hence inhibiting viral DNA synthesis during reproduction.[3]

It possesses in vitro activity against the following viruses:[21]

History

Cidofovir was discovered at the Institute of Organic Chemistry and Biochemistry, Prague, by Antonín Holý, and developed by Gilead Sciences[22] and is marketed with the brand name Vistide by Gilead in the USA, and by Pfizer elsewhere.

Synthesis

Cidofovir can be synthesized from a pyrimidone derivative and a protected derivative of glycidol.[23]

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See also

  • Brincidofovir, a novel prodrug of cidofovir that can be taken orally

References

  1. ↑ Cundy, Kenneth C. "Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir." Clinical Pharmacokinetics 36.2 (1999): 127-43.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ 17.0 17.1 http://www.gilead.com/~/media/Files/pdfs/medicines/other/vistide/vistide.pdf
  18. ↑ Lacy, S. "Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys.
  19. ↑ 19.0 19.1 19.2 Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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