Valaciclovir

Valaciclovir
Systematic (IUPAC) name
(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
Clinical data
Trade names Valtrex
AHFS/Drugs.com monograph
MedlinePlus a695010
Licence data US FDA:link
  • AU: B3
  • US: B (No risk in non-human studies)
Oral
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Hepatic (to aciclovir)
Half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Renal 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
124832-26-4 
J05AB11
PubChem CID 60773
DrugBank DB00577 Yes
ChemSpider 54770 Yes
UNII MZ1IW7Q79D Yes
KEGG D00398 
ChEBI CHEBI:35854 Yes
ChEMBL CHEMBL1349 Yes
NIAID ChemDB 070982
Chemical data
Formula C13H20N6O4
324.336 g/mol
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Valaciclovir (INN) or valacyclovir (USAN) 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. 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.[1]

Pharmacology

Mechanism of action

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.[2]

Microbiology

Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:[3]

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.[4][5][6] It is inactive against latent viruses in nerve ganglia.

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.[7]

It also is used for herpes B virus postexposure prophylaxis.[8]

Ingredients and dosage

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.[9]

Clinical use

Indications

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:[10]

It has shown promise as a treatment for infectious mononucleosis,[4][13][6] 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.[10]

References

  1. ↑ Ahmed, Rumman (2009-11-27). "Ranbaxy Launches Generic Valtrex in U.S.". The Wall Street Journal. Retrieved 2010-01-16.
  2. ↑ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm
  3. ↑ 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.
  4. ↑ 4.0 4.1 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
  5. ↑ "Adverse Effects Caused by Regular Use of Valacyclovir". Retrieved February 1, 2015.
  6. ↑ 6.0 6.1 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.
  7. ↑ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.
  8. ↑ CDC - Herpes B virus: First Aid and Treatment
  9. ↑ "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. September 2008. Retrieved 7 May 2009.
  10. ↑ 10.0 10.1 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  11. ↑ 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 1 January 2012.
  12. ↑ 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.
  13. ↑ Simon, Michael W.; Robert G. Deeter and 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.