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 2021, it was the 114th most commonly prescribed medication in the United States, with more than 5 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 2021, it was the 114th 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]

Related Research Articles

<span class="mw-page-title-main">Varicella zoster virus</span> Herpes virus that causes chickenpox and shingles

Varicella zoster virus (VZV), also known as human herpesvirus 3 or Human alphaherpesvirus 3 (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles in adults but rarely in children. VZV infections are species-specific to humans. The virus can survive in external environments for a few hours.

<span class="mw-page-title-main">Shingles</span> Viral disease caused by the varicella zoster virus

Shingles, also known as herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. Two to four days before the rash occurs there may be tingling or local pain in the area. Other common symptoms are fever, headache, and tiredness. The rash usually heals within two to four weeks; however, some people develop ongoing nerve pain which can last for months or years, a condition called postherpetic neuralgia (PHN). In those with poor immune function the rash may occur widely. If the rash involves the eye, vision loss may occur.

<span class="mw-page-title-main">Keratitis</span> Medical condition

Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired eyesight, photophobia, red eye and a 'gritty' sensation. Diagnosis of infectious keratitis is usually made clinically based on the signs and symptoms as well as eye examination, but corneal scrapings may be obtained and evaluated using microbiological culture or other testing to identify the causative pathogen.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox, and shingles

Aciclovir, also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

<span class="mw-page-title-main">Valganciclovir</span> Antiviral medication

Valganciclovir, sold under the brand name Valcyte among others, is an antiviral medication used to treat cytomegalovirus (CMV) infection in those with HIV/AIDS or following organ transplant. It is often used long term as it only suppresses rather than cures the infection. Valganciclovir is taken by mouth.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Brivudine</span> Chemical compound

Brivudine is an antiviral drug used in the treatment of herpes zoster ("shingles"). Like other antivirals, it acts by inhibiting replication of the target virus.

<span class="mw-page-title-main">Herpes simplex virus</span> Species of virus

Herpes simplex virus1 and 2, also known by their taxonomic names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are very common and contagious. They can be spread when an infected person begins shedding the virus.

<span class="mw-page-title-main">Genital herpes</span> Infection by herpes simplex viruses of the genitals

Genital herpes is a herpes infection of the genitals caused by the herpes simplex virus (HSV). Most people either have no or mild symptoms and thus do not know they are infected. When symptoms do occur, they typically include small blisters that break open to form painful ulcers. Flu-like symptoms, such as fever, aching, or swollen lymph nodes, may also occur. Onset is typically around 4 days after exposure with symptoms lasting up to 4 weeks. Once infected further outbreaks may occur but are generally milder.

<span class="mw-page-title-main">Foscarnet</span> Chemical compound

Foscarnet (phosphonomethanoic acid), known by its brand name Foscavir, is an antiviral medication which is primarily used to treat viral infections involving the Herpesviridae family. It is classified as a pyrophosphate analog DNA polymerase inhibitor. Foscarnet is the conjugate base of a chemical compound with the formula HO2CPO3H2 (Trisodium phosphonoformate).

Herpes gladiatorum is one of the most infectious of herpes-caused diseases, and is transmissible by skin-to-skin contact. The disease was first described in the 1960s in the New England Journal of Medicine. It is caused by contagious infection with human herpes simplex virus type 1 (HSV-1), which more commonly causes oral herpes. Another strain, HSV-2 usually causes genital herpes, although the strains are very similar and either can cause herpes in any location.

Acute retinal necrosis (ARN) is a medical inflammatory condition of the eye. The condition presents itself as a necrotizing retinitis. The inflammation onset is due to certain herpes viruses, varicella zoster virus (VZV), herpes simplex virus (HSV-1 and HSV-2) and Epstein–Barr virus (EBV).

<span class="mw-page-title-main">Sorivudine</span> Chemical compound

Sorivudine (INN), is a nucleoside analogue antiviral drug, marketed under trade names such as Usevir and Brovavir (BMS). It is used for the treatment of varicella zoster virus infections.

<span class="mw-page-title-main">Thymidine kinase from herpesvirus</span>

Thymidine kinase from herpesvirus is a sub-family of thymidine kinases that catalyses the transfer of phospho group of ATP to thymidine to generate thymidine monophosphate, which serves as a substrate during viral DNA replication.

<span class="mw-page-title-main">Herpes</span> Viral disease caused by herpes simplex viruses

Herpes simplex, often known simply as herpes, is a viral infection caused by the herpes simplex virus. Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are oral herpes and genital herpes, though other forms also exist.

<span class="mw-page-title-main">Cold sore</span> Herpes simplex virus infection of the lip

A cold sore is a type of herpes infection caused by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack may also be accompanied by fever, sore throat, and enlarged lymph nodes. The rash usually heals within ten days, but the virus remains dormant in the trigeminal ganglion. The virus may periodically reactivate to create another outbreak of sores in the mouth or lip.

<span class="mw-page-title-main">Herpes esophagitis</span> Medical condition

Herpes esophagitis is a viral infection of the esophagus caused by Herpes simplex virus (HSV).

<span class="mw-page-title-main">Herpes simplex keratitis</span> Medical condition

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.

<span class="mw-page-title-main">Pritelivir</span> Chemical compound

Pritelivir is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. Pritelivir is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

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 (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. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN   9780857113382.
  7. 1 2 "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  8. 1 2 "Valacyclovir - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  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 1989-03-22, 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. ↑ Ahmed R (27 November 2009). "Ranbaxy Launches Generic Valtrex in U.S." The Wall Street Journal . Retrieved 16 January 2010.
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