Valaciclovir

drugbox
IUPAC_name = 2- [(2-amino-6-oxo-3,9-dihydropurin-9-yl)methoxy]
ethyl-2-amino-3-methyl-butanoate

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width = 192
CAS_number = 124832-26-4
ChemSpiderID = 54770
ATC_prefix = J05
ATC_suffix = AB11
ATC_supplemental =
PubChem = 60773
DrugBank = APRD00697
C=13 | H=20 | N=6 | O=4
molecular_weight = 324.336 g/mol
smiles = Nc1nc(=O)c2ncn(COCCOC(=O) [C@@H] (N)C(C)C)c2 [nH] 1
bioavailability = 55%
protein_bound = 13–18%
metabolism = Hepatic (to aciclovir)
elimination_half-life = <30 minutes (valaciclovir);
2.5-3.6 hours (aciclovir)
excretion = Renal 40–50% (aciclovir),
faecal 47% (aciclovir)
pregnancy_category = B3 (Au), B (U.S.)
legal_status = S4 (Au), POM (UK), ℞-only (U.S.)
routes_of_administration = Oral

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.

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 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:O'Brien JJ, Campoli-Richards DM. Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989;37(3):233-309. PMID 2653790]
*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. [Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392] [Simon et al. (March 2003) The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study. "International Pediatrics." Vol. 18, No. 3. pp. 164-169.] [cite journal |author=Balfour HH, Hokanson KM, Schacherer RM, "et al" |title=A virologic pilot study of valacyclovir in infectious mononucleosis |journal=J. Clin. Virol. |volume=39 |issue=1 |pages=16–21 |year=2007 |pmid=17369082 |doi=10.1016/j.jcv.2007.02.002] 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.Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4]

Ingredients

Valtrex is offered in 500mg and 1gram 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. [ [http://us.gsk.com/products/assets/us_valtrex.pdf Valtrex Prescribing Information] . GlaxoSmithKline, October 2007.]

Clinical use

Indications

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3]
* 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

It has shown promise as a treatment for infectious mononucleosis [Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392] [Simon et al. (March 2003) The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study. "International Pediatrics." Vol. 18, No. 3. pp. 164-169.] [Balfour et al. (May 2007) A virologic pilot study of valacyclovir in infectious mononucleosis. "Journal of Clinical Virology." Volume 39, Issue 1. pp. 16-21.] 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, anal leakage and/or 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.

Valaciclovir is contraindicated in immuno-suppressed patients such as those infected with HIV as it may cause thrombotic thrombocytopenic purpura and hemolytic uremic syndromes resulting in kidney failure. Aciclovir is preferred in these patients.

References

External links

* [http://www.valtrex.com Valtrex website]