Valaciclovir

Valaciclovir
Clinical data
Trade names Valtrex
AHFS/Drugs.com Monograph
MedlinePlus a695010
License data
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral
ATC code J05AB11 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Hepatic (to aciclovir)
Biological half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Renal 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
CAS Number 124832-26-4 N
PubChem (CID) 60773
IUPHAR/BPS 4824
DrugBank DB00577 YesY
ChemSpider 54770 YesY
UNII MZ1IW7Q79D YesY
KEGG D00398 N
ChEBI CHEBI:35854 YesY
ChEMBL CHEMBL1349 YesY
NIAID ChemDB 070982
ECHA InfoCard 100.114.479
Chemical and physical data
Formula C13H20N6O4
Molar mass 324.336 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Valaciclovir, also spelled valacyclovir, is an antiviral drug used in the management of herpes simplex, herpes zoster (shingles), and herpes B.

It is a prodrug, being converted in vivo to aciclovir.

Valaciclovir was approved for medical use in 1995.[1] It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.[2]

Medical use

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:[3]

It has shown promise as a treatment for infectious mononucleosis,[6][7][8] and is preventively administered in suspected cases of herpes B virus exposure.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with valaciclovir therapy are the same as for aciclovir, its active metabolite, and include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.[3]

Mechanism of action

Valaciclovir belongs from a family of molecules first described and patented by P.Cornaglia Ferraris in 1982 (patents EP0077460 A2, CA1258149A1, DE3273785D1, EP0077460A3, EP0077460B1, US4567182). Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir (10–20%). It is converted by esterases to the active drug aciclovir, as well as the amino acid valine, via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinases. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.[9]


Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:[10]

The drug is predominantly active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV; however, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.[6][7][8] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.[10]

To date, resistance to valaciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase, and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.[11]

It also is used for herpes B virus postexposure prophylaxis.[12]

Chemistry

Valtrex is offered in 250 mg, 500 mg, and 1 gram tablets, the active ingredient being valacyclovir hydrochloride, with the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.[13]


References

  1. ↑ Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  2. ↑ Ahmed, Rumman (November 27, 2009). "Ranbaxy Launches Generic Valtrex in U.S.". The Wall Street Journal. Retrieved January 16, 2010.
  3. 1 2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  4. ↑ Lille, H. Martina; Wassilew, Sawko W. (2006). "Antiviral therapies of shingles in dermatology". In Gross, Gerd; Doerr, H.W. Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
  5. ↑ Elad S, Zadik Y, Hewson I, et al. (August 2010). "A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea". Support Care Cancer. 18 (8): 993–1006. doi:10.1007/s00520-010-0900-3. PMID 20544224.
  6. 1 2 Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
  7. 1 2 Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study" (PDF). International Pediatrics. 18 (3): 164–169.
  8. 1 2 Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". Journal of Clinical Virology. 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082.
  9. ↑ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm
  10. 1 2 O'Brien JJ, Campoli-Richards DM (March 1989). "Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy". Drugs. 37 (3): 233–309. doi:10.2165/00003495-198937030-00002. PMID 2653790.
  11. ↑ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.
  12. ↑ "B Virus—First Aid and Treatment—Herpes B—CDC". Retrieved June 6, 2015.
  13. ↑ "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. September 2008. Retrieved May 7, 2009.
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