Cidofovir
|
|
| 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
|
- AU: Prescription Only (S4)
- CA: ℞-only
- UK: Prescription-only (POM)
- US: ℞-only
|
|
Routes of
administration
|
IV |
| Pharmacokinetic data |
| Bioavailability |
complete |
| Protein binding |
<6% |
| Half-life |
2.6 hours |
| Excretion |
renal
The above pharmacokinetic parameters are measured for cidofovir used in conjunction with probenecid.[1] |
| Identifiers |
|
CAS Registry Number
|
113852-37-2 Y |
|
ATC code
|
J05AB12 |
| PubChem |
CID 60613 |
| DrugBank |
DB00369 Y |
| ChemSpider |
54636 Y |
| UNII |
768M1V522C Y |
| ChEBI |
CHEBI:3696 Y |
| ChEMBL |
CHEMBL152 Y |
| NIAID ChemDB |
001049 |
| Chemical data |
| Formula |
C8H14N3O6P |
|
Molecular mass
|
279.187 g/mol |
SMILES
- O=C1/N=C(\C=C/N1C[C@H](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 Y
Key:VWFCHDSQECPREK-LURJTMIESA-N Y
|
| Physical data |
| Melting point |
260 °C (500 °F) |
| Specific rotation |
-97.3 |
| Y (what is this?) (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]
Contents
- 1 Medical uses
- 2 Administration
- 3 Side effects
- 3.1 Contraindications
- 3.2 Interactions
- 4 Mechanism of action
- 5 History
- 6 Synthesis
- 7 See also
- 8 References
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]
- 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.[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]
- 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[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]
See also
- Brincidofovir, a novel prodrug of cidofovir that can be taken orally
References
- ^ Cundy, Kenneth C. "Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir." Clinical Pharmacokinetics 36.2 (1999): 127-43.
- ^ a b c d e "Vistide (cidofovir) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 4 February 2014.
- ^ a b c d e f g h "Product Information VISTIDE®". TGA eBusiness Services. Gilead Sciences Pty Ltd. 3 September 2013. Retrieved 5 February 2014.
- ^ Chilukuri, S; Rosen, T (Apr 2003). "Management of acyclovir-resistant herpes simplex virus.". Dermatologic clinics 21 (2): 311–20. doi:10.1016/S0733-8635(02)00093-1. PMID 12757254.
- ^ Segarra-Newnham M, Vodolo KM (June 2001). "Use of cidofovir in progressive multifocal leukoencephalopathy". Ann Pharmacother 35 (6): 741–4. doi:10.1345/aph.10338. PMID 11408993.
- ^ De Gascun, C. F.; Carr, M. J. (2013). "Human polyomavirus reactivation: Disease pathogenesis and treatment approaches". Clinical and Developmental Immunology 2013: 373579. doi:10.1155/2013/373579. PMC 3659475. PMID 23737811. edit
- ^ De Clercq E (July 2002). "Cidofovir in the treatment of poxvirus infections". Antiviral Res. 55 (1): 1–13. doi:10.1016/S0166-3542(02)00008-6. PMID 12076747.
- ^ Bradbury, J (March 2002). "Orally available cidofovir derivative active against smallpox.". Lancet 359 (9311): 1041. doi:10.1016/S0140-6736(02)08115-1. PMID 11937193.
- ^ Magee, WC; Hostetler, KY; Evans, DH (August 2005). "Mechanism of Inhibition of Vaccinia Virus DNA Polymerase by Cidofovir Diphosphate" (PDF). Antimicrobial Agents and Chemotherapy 49 (8): 3153–3162. doi:10.1128/AAC.49.8.3153-3162.2005. PMC 1196213. PMID 16048917.
- ^ Araya CE, Lew JF, Fennell RS, Neiberger RE, Dharnidharka VR (February 2006). "Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy". Pediatr Transplant 10 (1): 32–7. doi:10.1111/j.1399-3046.2005.00391.x. PMID 16499584.
- ^ Broekema FI, Dikkers FG (August 2008). "Side-effects of cidofovir in the treatment of recurrent respiratory papillomatosis". Eur Arch Otorhinolaryngol 265 (8): 871–9. doi:10.1007/s00405-008-0658-0. PMC 2441494. PMID 18458927.
- ^ Soma MA, Albert DM (February 2008). "Cidofovir: to use or not to use?". Curr Opin Otolaryngol Head Neck Surg 16 (1): 86–90. doi:10.1097/MOO.0b013e3282f43408. PMID 18197029.
- ^ "Cidofovir Monograph for Professionals - Drugs.com". Drugs.com. American Society of Health-System Pharmacists. Retrieved 5 February 2014.
- ^ "Vistide : EPAR -Product Information" (PDF). European Medicines Agency. Gilead Sciences International Ltd. 7 November 2013. Retrieved 5 February 2014.
- ^ Liekens S, Gijsbers S, Vanstreels E, Daelemans D, De Clercq E, Hatse S (March 2007). "The nucleotide analog cidofovir suppresses basic fibroblast growth factor (FGF2) expression and signaling and induces apoptosis in FGF2-overexpressing endothelial cells". Mol. Pharmacol. 71 (3): 695–703. doi:10.1124/mol.106.026559. PMID 17158200.
- ^ Liekens S (2008). "Regulation of cancer progression by inhibition of angiogenesis and induction of apoptosis". Verh. K. Acad. Geneeskd. Belg. 70 (3): 175–91. PMID 18669159.
- ^ a b http://www.gilead.com/~/media/Files/pdfs/medicines/other/vistide/vistide.pdf
- ^ Lacy, S. "Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys.
- ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- ^ "Vistide (cidofovir)" (PDF) (package insert). Gilead Sciences. September 2010. DOSAGE AND ADMINISTRATION: Dosage.
- ^ Safrin, S; Cherrington, J; Jaffe, HS (September 1997). "Clinical uses of cidofovir". Reviews in Medical Virology 7 (3): 145–156. doi:10.1002/(SICI)1099-1654(199709)7:3<145::AID-RMV196>3.0.CO;2-0. PMID 10398479.
- ^ "Press Releases: Gilead". Retrieved 2007-12-05.
- ^ Brodfuehrer, P; Howell, Henry G.; Sapino, Chester; Vemishetti, Purushotham (1994). "A practical synthesis of (S)-HPMPC". Tetrahedron Letters 35 (20): 3243. doi:10.1016/S0040-4039(00)76875-4.
|
DNA virus antivirals (primarily J05, also S01AD and D06BB)
|
|
| Baltimore I |
| Herpesvirus |
DNA-synthesis
inhibitor |
| TK activated |
| Purine analogue |
- guanine (Aciclovir#/Valaciclovir
- Ganciclovir/Valganciclovir
- Penciclovir/Famciclovir)
|
|
| Pyrimidine analogue |
- uridine (Idoxuridine
- Trifluridine
- Edoxudine)
|
|
|
| Not TK activated |
|
|
|
| Other |
- Docosanol
- early protein (Fomivirsen)
- Tromantadine
|
|
|
| HPV/MC |
- Imiquimod/Resiquimod
- Podophyllotoxin
|
|
| Vaccinia |
|
|
| Poxviridae |
|
|
|
| Hepatitis B (VII) |
- Nucleoside analogues/NARTIs: Entecavir
- Lamivudine
- Telbivudine
- Clevudine
- Nucleotide analogues/NtRTIs: Adefovir
- Tenofovir
|
|
| Multiple/general |
| Nucleic acid inhibitors |
|
|
| Interferon |
- Interferon alfa 2b
- Peginterferon alfa-2a
|
|
| Multiple/unknown |
- Ribavirin#/Taribavirin†
- Moroxydine
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
Index of viral disease
|
|
| Description |
|
|
| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
|
|
| Treatment |
|
|
|
