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Valaciclovir

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Valaciclovir
Clinical data
Pregnancy
category
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability55%
Protein binding13–18%
MetabolismHepatic (to aciclovir)
Elimination half-life<30 minutes (valaciclovir);
2.5-3.6 hours (aciclovir)
ExcretionRenal 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
  • (S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.114.479 Edit this at Wikidata
Chemical and physical data
FormulaC13H20N6O4
Molar mass324.336 g/mol g·mol−1
3D model (JSmol)
  • Nc1nc(=O)c2ncn(COCCOC(=O)[C@@H](N)C(C)C)c2[nH]1

Valaciclovir (INN) or valacyclovir (USAN) is an antiviral drug used in the management of herpes simplex and herpes zoster (shingles). It is a prodrug, being converted in vivo to aciclovir. It is marketed by GlaxoSmithKline under the trade name Valtrex or Zelitrex.

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. Acyclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation 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.

Microbiology

Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:[1]

Activity 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.[2][3][4] 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.[5]

Ingredients

Valtrex is offered in 500 mg and 1gram 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.[6]

Clinical use

Indications

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:[7]

It has shown promise as a treatment for infectious mononucleosis[2][3][8] and is preventatively 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, anal leakage and/or 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.[7]

Valaciclovir is contraindicated in immuno-suppressed patients such as those infected with HIV as it may cause thrombotic thrombocytopenic purpura and hemolytic uremic syndromes resulting in kidney failure. Aciclovir is preferred in these patients.

Valaciclovir was recently approved for generic production. Teva, Mylan, Ranbaxy (an Indian company) will all have the generic versions on the market by the end of 2009 or sooner.

References

  1. ^ O'Brien JJ, Campoli-Richards DM (1989). "Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy". Drugs. 37 (3): 233–309. PMID 2653790. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)
  2. ^ a b 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
  3. ^ a b Simon, Michael W. (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. Retrieved May 7, 2009. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  4. ^ Balfour HH, Hokanson KM, Schacherer RM; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Sweetman, Sean C. (2005). Martindale: the complete drug reference. London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.[page needed]
  6. ^ "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. 2008. Retrieved May 7, 2009. {{cite web}}: Unknown parameter |month= ignored (help)
  7. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  8. ^ Balfour HH, Hokanson KM, Schacherer RM; et al. (2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082. {{cite journal}}: |access-date= requires |url= (help); Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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