Valaciclovir

Description

Valaciclovir (also known as BW256U87 or valaciclovir, and marketed under the trade name of Valtrexs by GlaxoSmithKline) is the hydrochloride salt of the L-valyl ester of aciclovir that was developed originally by Wellcome Research Laboratories. This aciclovir prodrug is rapidly and virtually completely converted to aciclovir following oral administration. As oral administration of valaciclovir results in aciclovir plasma levels nearly equivalent to those achieved by intravenous administration, its efficacy is superior to that of oral aciclovir for the treatment of zoster and equivalent to oral aciclovir in the treatment of first and recurrent episodes of genital herpes.

Chemical Properties

White Solid

Originator

Valcivir,Cipla Limited

Uses

The L-Valine ester prodrug of Acyclovir.

Valacyclovir (Valtrex) is the 1-valine ester (prodrug) of acyclovir that exhibits no activity until hydrolyzed in the intestinal wall or liver to acyclovir and its active metabolite. Its modified structure allows increased intestinal absorption and concomitant higher plasma levels of acyclovir. It demonstrates activity against HSV types 1 and 2, varicella-zoster virus, and cytomegalovirus. It exerts its effects by interfering with DNA synthesis through phosphorylation by viral thymidine kinase and subsequent inhibition of viral DNA polymerase, thereby inhibiting viral replication. Valtrex is indicated for the treatment of acute herpes zoster and recurrent genital herpes in immunocompetent adults. The most common side effects are headache, nausea, and vomiting.

Indications

Valacyclovir (Valtrex) is the 1-valine ester (prodrug) of acyclovir that exhibits no activity until hydrolyzed in the intestinal wall or liver to acyclovir and its active metabolite. Its modified structure allows increased intestinal absorption and concomitant higher plasma levels of acyclovir. It demonstrates activity against HSV types 1 and 2, varicella-zoster virus, and cytomegalovirus. It exerts its effects by interfering with DNA synthesis through phosphorylation by viral thymidine kinase and subsequent inhibition of viral DNA polymerase, thereby inhibiting viral replication. Valtrex is indicated for the treatment of acute herpes zoster and recurrent genital herpes in immunocompetent adults. The most common side effects are headache, nausea, and vomiting.
Valacyclovir is the only antiviral agent approved for herpes labialis, for a 3-day course in the episodic treatment of recurrent genital herpes (2). Valacyclovir is indicated for recurrent genital herpes and is administered at 500 mg twice daily for 3 days at the onset of prodromal symptoms or at the first sign of infection.

Definition

ChEBI: Valacyclovir is a L-valyl ester. It has a role as an antiviral drug. It is functionally related to a guanine.

Manufacturing Process

By dicyclohexylcarbodiimide catalyzed esterification of acyclovir (6H-purin-6- one, 1,9-dihydro-2-amino-9-((2-hydroxyethoxy)methyl)-) with the butyloxycarbonyl valine. Treatment of ester obtained with trifluoroacetic acid leads to scission of the BOC group to provide L-valine ester with 9-((2- hydroxyethoxy)methyl)guanine (valacyclovir).

brand name

Valtrex (GlaxoSmithKline).

Therapeutic Function

Antiviral

Biological Activity

valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5].

Pharmacology

Valacyclovir (Valtrex), a valine ester prodrug of acyclovir, has a bioavailability three to five times that of acyclovir. This is due to its improved gastrointestinal absorption compared to acyclovir. Valacyclovir is rapidly and almost completely converted to acyclovir after oral administration, with levels comparable to those of intravenous acyclovir. This allows for twice-daily dosing, which may improve compliance and ultimate clinical efficacy. It is more costly than acyclovir.

Clinical Use

Antiviral:
Herpes zoster and simplex
Prevention of cytomegalovirus (CMV) disease after renal transplantation

in vivo

for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: may alter ciclosporin levels; possibly increased risk of nephrotoxicity.
Mycophenolate: higher concentrations of both aciclovir and mycophenolic acid on concomitant administration.
Tacrolimus: possibly increased risk of nephrotoxicity

IC 50

value: 2.9 microg/ml (for hsv-1 w)[4]. valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5]. in vivo: for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].

Metabolism

Valaciclovir is readily absorbed from the gastrointestinal tract after oral doses, and is rapidly and almost completely converted to aciclovir and valine by first-pass intestinal or hepatic metabolism.
Aciclovir is converted to a small extent to the metabolites 9(carboxymethoxy)methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (8-OH-ACV) by aldehyde oxidase. Approximately 88
% of the total combined plasma exposure is attributable to aciclovir, 11
% to CMMG and 1
% to 8-OH-ACV. Valaciclovir is eliminated mainly as aciclovir and its metabolite 9- CMMG; less than 1
% of a dose of valaciclovir is excreted unchanged in the urine.

Toxicity evaluation

In general, the adverse reactions with valaciclovir are similar to those seen with its active metabolite, aciclovir. Preclinical toxicology studies with valaciclovir toxicology studies in animals showed no toxicity separate to that expected from the active metabolite. In a phase 1 study of valaciclovir dosed at either 1 or 2 g four times daily for 30 days, the main reported side-effects were gastrointestinal, with nausea, vomiting, diarrhea, and abdominal pain in up to onethird of patients; no renal or neurologic side-effects were notetoxd, but four patients developed grade 3 or 4 neutropenia. None of the sideeffects observed appeared to be drug related.

Raw materials

Preparation Products