Valaciclovir

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]

Valaciclovir
Clinical data
Trade namesValtrex, Zelitrex, others
Other namesvalacyclovir, valacyclovir hydrochloride (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa695010
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability55%
Protein binding13–18%
MetabolismLiver (to aciclovir)
Elimination half-life<30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
ExcretionKidney 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
IUPAC name
  • 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 InfoCard100.114.479
Chemical and physical data
FormulaC13H20N6O4
Molar mass324.341 g·mol−1
3D model (JSmol)
SMILES
  • O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
InChI
  • 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 Y
  • Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N Y
 NY (what is this?)  (verify)

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 2020, it was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[7][8]

Medical uses
Valtrex brand valaciclovir 500mg tablets

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

  • Oral and genital herpes simplex (treatment and prevention)
  • 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.[10]
  • Prevention of cytomegalovirus following organ transplantation
  • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[11]
  • Chickenpox in children (ages 2–18)[1]

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, they are expensive, they risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects.[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.

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 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[7][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 U.S. since November 2009.[25]

References
  1. "Valtrex- valacyclovir hydrochloride tablet, film coated". DailyMed. 14 June 2021. Retrieved 22 May 2022.
  2. "Valacyclovir Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 17 March 2019.
  3. Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 978-1437727029.
  4. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
  5. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  6. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
  7. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  8. "Valacyclovir - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  9. Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  10. Lille, H. Martina; Wassilew, Sawko W. (2006). "Antiviral therapies of shingles in dermatology". In Gross, Gerd; Doerr, H.W. (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. Balfour et al. (December 2005) A controlled trial of valaciclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., 18 December 2005. Abstract V1392
  13. 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.
  14. 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. "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. 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, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.
  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. EP patent 308065, Krenitsky, Thomas Anthony & Beauchamp, Lilia Marie, "Therapeutic nucleosides", published 1989-03-22, assigned to Wellcome Foundation
  24. Vardanyan, Ruben; Hruby, Victor (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. Ahmed, Rumman (27 November 2009). "Ranbaxy Launches Generic Valtrex in U.S." The Wall Street Journal. Retrieved 16 January 2010.
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