Valaciclovir

Valaciclovir

Systematic (IUPAC) name
(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
Clinical data
Trade names	Valtrex
AHFS/Drugs.com	monograph
MedlinePlus	a695010
Licence data	US FDA:link
Pregnancy category	AU: B3 US: B (No risk in non-human studies)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Routes of administration	Oral
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 N
ATC code	J05AB11 (WHO)
PubChem	CID: 60773
IUPHAR/BPS	4824
DrugBank	DB00577 Y
ChemSpider	54770 Y
UNII	MZ1IW7Q79D Y
KEGG	D00398 N
ChEBI	CHEBI:35854 Y
ChEMBL	CHEMBL1349 Y
NIAID ChemDB	070982
Chemical data
Formula	C13H20N6O4
Molecular mass	324.336 g/mol
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)

Valaciclovir (INN) or valacyclovir (USAN) is an antiviral drug used in the management of herpes simplex, herpes zoster (shingles), and herpes B. It is a prodrug, being converted in vivo to aciclovir. It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.

Pharmacology

Mechanism of action

Valaciclovir belongs from a family of molecules first described and patented by P.Cornaglia Ferraris in 1982 (patents EP0077460 A2, CA1258149A1, DE3273785D1, EP0077460A3, EP0077460B1, US4567182). 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. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation of aciclovir 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)

The drug 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.

It also is used for herpes B virus postexposure prophylaxis.

Ingredients and dosage

Valtrex is offered in 250 mg, 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

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): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.

• Prevention of cytomegalovirus following organ transplantation
• Prophylaxis against herpesviruses in immunocompromised patients (such as patients undergoing cancer chemotherapy)

It has shown promise as a treatment for infectious mononucleosis, and is preventively 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.