Valaciclovir

Valaciclovir

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Systematic (IUPAC) name
(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
Clinical data
Pregnancy category	B3 (Au), B (U.S.)
Routes of administration	Oral
Legal status
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability	55%
Protein binding	13–18%
Metabolism	Hepatic (to aciclovir)
Biological half-life	<30 minutes (valaciclovir); 2.5-3.6 hours (aciclovir)
Excretion	Renal 40–50% (aciclovir), faecal 47% (aciclovir)
Identifiers
CAS Number	124832-26-4
ATC code	J05AB11 (WHO)
PubChem	CID 60773
DrugBank	APRD00697
ChemSpider	54770
Chemical data
Formula	C13H20N6O4
Molar mass	324.336 g/mol[[]]

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. As of November 25, 2009 (2009 -11-25), Valacyclovir is being marketed in generic form in the United States by Ranbaxy Laboratories.

Chemistry

Valaciclovir is prepared, starting from the natural proteinogenic amino acid (L)-valine.

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:

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

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. 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.

Ingredients

Valtrex is offered in 500 mg and 1 gram 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.

Clinical use

Indications

File:Valtrex pill.jpg

Valtrex brand valaciclovir 500mg tablets

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

• Oral and Genital herpes simplex (treatment and prophylaxis)
• Reduction of HSV transmission from people with recurrent infection to uninfected individuals
• Herpes zoster (shingles)
• Prevention of CMV disease following organ transplantation
• Prophylaxis against herpesvirus' in immunocompromised patients (such as patients undergoing cancer chemotherapy)

It has shown promise as a treatment for infectious mononucleosis 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 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.

References

de:Valaciclovir zh:伐昔洛韦