Valaciclovir

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Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles).<ref name=AHFS2019/> It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019/>

Common side effects include headache and vomiting.<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Severe side effects may include kidney problems.<ref name=AHFS2019/> Use in pregnancy appears to be safe.<ref name=AHFS2019/> It is a prodrug, which works after being converted to aciclovir in a person's body.<ref name=AHFS2019/>

Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0">Template:Cite book</ref><ref name=Fis2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name=BNF76>Template:Cite book</ref> In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5Template:Nbspmillion prescriptions.<ref name="Top 300">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="ClinCalc Valacyclovir">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

File:Valtrex pill.jpg

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:<ref name="AMH2006">Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. Template:ISBNTemplate:Page needed</ref>

• 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.<ref>Template:Cite book</ref>
• Prevention of cytomegalovirus following organ transplantation
• Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)<ref name="Cancer">Template:Cite journal</ref>
• Chickenpox in children (ages 2–18)<ref name="Valtrex FDA label" />

It has shown promise as a treatment for infectious mononucleosis<ref name=balfour2005/><ref name=simon2003>Template:Cite journal</ref><ref name="pmid17369082" /> and is preventively administered in suspected cases of herpes B virus exposure.<ref name=":3" />

Bell's palsy does not seem to benefit from using valaciclovir as its only treatment.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="AMH2006" />

Pharmacology

Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.<ref name="Valtrex FDA label" /> 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.<ref name="Valtrex FDA label" />

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.<ref name="Valtrex FDA label" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:<ref name="OBrien1989">Template:Cite journal</ref>

• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein–Barr virus (EBV)
• Cytomegalovirus (CMV)

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.<ref name=balfour2005>Template:Cite conference</ref><ref name=simon2003 /><ref name="pmid17369082">Template:Cite journal</ref> 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.<ref name="pmid27933614">Template:Cite journal</ref> Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia.<ref name="OBrien1989">Template:Cite journal</ref>

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.<ref name="Martindale34">Template:Cite bookTemplate:Page needed</ref>

It also is used for herpes B virus postexposure prophylaxis.<ref name=":3">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Chemistry

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

File: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.<ref>Template:Cite patent</ref><ref>Template:Cite book</ref>

History

Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0" /><ref name="Fis2006" /> It is available as a generic medication.<ref name="BNF76" /> In 2022, it was the 113th most commonly prescribed medication in the United States, with more than 5Template:Nbspmillion prescriptions.<ref name="Top 300" /><ref name="ClinCalc Valacyclovir" />

Society and culture

Brand names

It is marketed by GlaxoSmithKline under the brand names Valtrex<ref name="Valtrex FDA label" /> and Zelitrex. Valaciclovir has been available as a generic drug in the US since November 2009.<ref>Template:Cite news</ref>