Valaciclovir

Last updated

Valaciclovir
Valaciclovir structure.svg
Clinical data
Trade names Valtrex, Zelitrex, others
Other namesvalacyclovir, valacyclovir hydrochloride (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a695010
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
Drug class Antiviral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Liver (to aciclovir)
Elimination half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Kidney 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
  • 2-[(2-Amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.479 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H20N6O4
Molar mass 324.341 g·mol−1
3D model (JSmol)
  • O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
  • InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1 Yes check.svgY
  • Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). [2] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. [2] It is taken by mouth. [2]

Contents

Common side effects include headache and vomiting. [2] Severe side effects may include kidney problems. [2] Use in pregnancy appears to be safe. [2] It is a prodrug, which works after being converted to aciclovir in a person's body. [2]

Valaciclovir was patented in 1987 and came into medical use in 1995. [3] [4] It is on the World Health Organization's List of Essential Medicines. [5] It is available as a generic medication. [6] In 2023, it was the 98th most commonly prescribed medication in the United States, with more than 7 million prescriptions. [7] [8]

Medical uses

Valtrex brand valaciclovir 500mg tablets Valtrex pill.jpg
Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including: [9]

It has shown promise as a treatment for infectious mononucleosis [12] [13] [14] and is preventively administered in suspected cases of herpes B virus exposure. [15]

Bell's palsy does not seem to benefit from using valaciclovir as its only treatment. [16] [17]

Adverse effects

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They 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. [9]

Pharmacology

Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir. [1] It is converted by esterases to the active drug, aciclovir, and the amino acid valine via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases. [1]

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase. [1] 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 metabolized within the cell, possibly by cellular phosphatases. [18]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity: [19]

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valaciclovir has 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. [12] [13] [14] Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus. [20] Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia. [19]

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity. [21]

It also is used for herpes B virus postexposure prophylaxis. [15] [22]

Chemistry

Details of the synthesis of valaciclovir were first published by scientists from the Wellcome Foundation.

Valaciclovir sythesis.svg

Aciclovir was esterified with a carboxybenzyl protected valine, using dicyclohexylcarbodiimide as the dehydrating agent. In the final step, the protecting group was removed by hydrogenation using a palladium on alumina catalyst. [23] [24]

History

Valaciclovir was patented in 1987 and came into medical use in 1995. [3] [4] It is available as a generic medication. [6] In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions. [25] [8]

Society and culture

Brand names

It is marketed by GlaxoSmithKline under the brand names Valtrex [1] and Zelitrex. Valaciclovir has been available as a generic drug in the US since November 2009. [26]

References

  1. 1 2 3 4 5 6 "Valtrex- valacyclovir hydrochloride tablet, film coated". DailyMed. 14 June 2021. Retrieved 22 May 2022.
  2. 1 2 3 4 5 6 7 "Valacyclovir Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 17 March 2019.
  3. 1 2 Long SS, Pickering LK, Prober CG (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN   978-1437727029.
  4. 1 2 Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN   9783527607495.
  5. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  6. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN   9780857113382.
  7. ↑ "Top 300 of 2023". ClinCalc. Archived from the original on 12 August 2025. Retrieved 12 August 2025.
  8. 1 2 "Valacyclovir Drug Usage Statistics, United States, 2013 - 2023". ClinCalc. Retrieved 18 August 2025.
  9. 1 2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN   0-9757919-2-3 [ page needed ]
  10. ↑ Lille HM, Wassilew SW (2006). "Antiviral therapies of shingles in dermatology". In Gross G, Doerr H (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. Vol. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN   978-3-8055-7982-7 . Retrieved 1 January 2012.
  11. ↑ Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, 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. S2CID   2969472.
  12. 1 2 Balfour HH, Hokanson KM, Schacherer RM (December 2005). A controlled trial of valacyclovir in infectious mononucleosis. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC. pp. 16–19. Abstract V1392.
  13. 1 2 Simon MW, Deeter RG, Shahan B (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study". International Pediatrics. 18 (3): 164–169 – via ResearchGate.
  14. 1 2 Balfour HH, Hokanson KM, Schacherer RM, Fietzer CM, Schmeling DO, Holman CJ, 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.
  15. 1 2 "Herpes B Virus: Information For Healthcare Providers". U.S. Centers for Disease Control and Prevention (CDC). 31 January 2019. Retrieved 22 May 2022.
  16. ↑ Baugh RF, Basura GJ, Ishii LE, Schwartz SR, Drumheller CM, Burkholder R, et al. (November 2013). "Clinical practice guideline: Bell's palsy". Otolaryngology–Head and Neck Surgery. 149 (3_suppl): S1 –S27. doi: 10.1177/0194599813505967 . PMID   24189771. S2CID   36915347.
  17. ↑ Gagyor I, Madhok VB, Daly F, Sullivan F (September 2019). "Antiviral treatment for Bell's palsy (idiopathic facial paralysis)". Cochrane Database Syst Rev. 2019 (9): CD001869. doi:10.1002/14651858.CD001869.pub9. PMC   6726970 . PMID   31486071.
  18. ↑ "Valaciclovir (VCV) - USCN LIFE SCIENCE INC". www.uscnk.us. Archived from the original on 3 December 2014.
  19. 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. S2CID   240858022.
  20. ↑ De Paor M, O'Brien K, Smith SM (2016). "Antiviral agents for infectious mononucleosis (glandular fever)". The Cochrane Database of Systematic Reviews . 2016 (12): CD011487. doi:10.1002/14651858.CD011487.pub2. PMC   6463965 . PMID   27933614.
  21. ↑ Sweetman SC, ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN   0-85369-550-4. OCLC   56903116.[ page needed ]
  22. ↑ Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE (November 2002). "Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1)". Clin Infect Dis. 35 (10): 1191–203. doi: 10.1086/344754 . PMID   12410479. S2CID   4652818.
  23. ↑ EPpatent 308065,Krenitsky, Thomas Anthony&Beauchamp, Lilia Marie,"Therapeutic nucleosides",published 22 March 1989, assigned to Wellcome Foundation
  24. ↑ Vardanyan R, Hruby V (2016). "34: Antiviral Drugs". Synthesis of Best-Seller Drugs. p. 709. doi: 10.1016/B978-0-12-411492-0.00034-1 . ISBN   9780124114920. S2CID   75449475.
  25. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  26. ↑ Ahmed R (27 November 2009). "Ranbaxy Launches Generic Valtrex in U.S." The Wall Street Journal . Retrieved 16 January 2010.
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