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Cidofovir

Clinical data
Trade names	Vistide
AHFS/Drugs.com	Monograph
Pregnancy category	AU: D
Routes of administration	Intravenous
ATC code	J05AB12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: WARNINGRx-only
Pharmacokinetic data
Bioavailability	complete
Protein binding	<6%
Elimination 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.
Identifiers
IUPAC name ({oxy}methyl)phosphonic acid
CAS Number	113852-37-2
PubChem CID	60613
DrugBank	DB00369
ChemSpider	54636
UNII	768M1V522C
KEGG	C06909
ChEBI	CHEBI:3696
ChEMBL	ChEMBL152
NIAID ChemDB	001049
CompTox Dashboard (EPA)	DTXSID3043734
ECHA InfoCard	100.166.433
Chemical and physical data
Formula	C8H14N3O6P
Molar mass	279.189 g·mol
3D model (JSmol)	Interactive image
Specific rotation	-97.3
Melting point	260 °C (500 °F)
SMILES O=C1/N=C(\C=C/N1C(OCP(=O)(O)O)CO)N
InChI 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 Key:VWFCHDSQECPREK-LURJTMIESA-N
(verify)

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

Cidofovir was approved for medical use in 1996.

Medical use

DNA virus

Its only indication that has received regulatory approval worldwide is cytomegalovirus retinitis. Cidofovir has also shown efficacy in the treatment of aciclovir-resistant HSV infections. Cidofovir has also been investigated as a treatment for progressive multifocal leukoencephalopathy with successful case reports of its use. Despite this, the drug failed to demonstrate any efficacy in controlled studies. Cidofovir might have anti-smallpox efficacy and might be used on a limited basis in the event of a bioterror incident involving smallpox cases. Brincidofovir, a cidofovir derivative with much higher activity against smallpox that can be taken orally has been developed. 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. Cidofovir shows anti-BK virus activity in a subgroup of transplant recipients. Cidofovir is being investigated as a complementary intralesional therapy against papillomatosis caused by HPV.

It first received FDA approval on 26 June 1996, TGA approval on 30 April 1998 and EMA approval on 23 April 1997.

It has been used topically to treat warts.

Other

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

Administration

Cidofovir is only available as an intravenous formulation. Cidofovir is to be administered with probenecid which decreases side effects to the kidney. Probenecid mitigates nephrotoxicity by inhibiting organic anion transport of the proximal tubule epithelial cells of the kidney. In addition, hydration must be administered to patients receiving cidofovir. 1 liter of normal saline is recommended in conjunction with each dose of cidofovir.

Side effects

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

• Nausea
• Vomiting
• Neutropenia
• Hair loss
• Weakness
• Headache
• Chills
• Decreased intraocular pressure
• Uveitis
• Iritis

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

Contraindications

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

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. 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.

Mechanism of action

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

It possesses in vitro activity against the following viruses:

• Human herpesviruses
• Adenoviruses
• Human poxviruses (including the smallpox virus)
• Human papillomavirus

History

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

Synthesis

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

See also

• Brincidofovir, a prodrug of cidofovir

References

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• Gilead Sciences
• Anti-herpes virus drugs
• Pyrimidones
• Amines
• Ethers
• Phosphonic acids
• Primary alcohols