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
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability 55%
    Protein binding 13–18%
    Metabolism Hepatic (to aciclovir)
    Elimination half-life <30 minutes (valaciclovir);
    2.5–3.6 hours (aciclovir)
    Excretion Renal 40–50% (aciclovir),
    faecal 47% (aciclovir)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    NIAID ChemDB
    ECHA InfoCard 100.114.479 Edit this at Wikidata
    Chemical and physical data
    Formula C13H20N6O4
    Molar mass 324.336 g/mol
    3D model (JSmol)
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    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]

    • Oral and genital herpes simplex (treatment and prophylaxis)
    • Reduction of HSV transmission from people with recurrent infection to uninfected individuals
    • Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days. [4]

    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 to a family of molecules first described and patented by Paolo 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%5Bpermanent+dead+link%5D
    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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