Valaciclovir

Absorption

After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food .

Toxicity

LD50 Oral
Rat – 903.5 mg/kg
Carcinogenesis, Mutagenesis, Impairment of Fertility
Valacyclovir was noncarcinogenic in lifetime carcinogenicity assays at single daily gavage doses of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. No clinically significant difference in the incidence of tumors between treated and control animals was observed, and valacyclovir was not found to shorten the latency period of tumors. Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. An in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study was negative .
In the mouse lymphoma assay, valacyclovir was not found to be mutagenic without metabolic activation, however, in the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was also found to be mutagenic in a mouse micronucleus assay .
Valacyclovir did not impair fertility or reproduction in rats at 6 times the normal concentrations in human plasma .
Use in pregnancy
Valacyclovir is categorized as a pregnancy category B drug. There are insufficient well-controlled studies of valacyclovir in pregnant women. The general rate of birth defects in infants exposed to acyclovir in-utero is comparable to the rate for infants measured in the general population. This drug should be used during pregnancy only if the potential benefit justifies the possible fetal risk .
Use in nursing
Acyclovir, a major metabolite of valacyclovir, was excreted in breastmilk at lower concentrations when a normal therapeutic dose of valacyclovir was administered. Exercise caution when acyclovir is used while nursing .
A note on renal function and toxicity in elderly patients
Elderly patients and patients with decreased renal function are at increased risk of valacyclovir toxicity, which can sometimes lead to central nervous system effects, such as encephalopathy, agitation, dysarthria, mania, and psychosis, among other effects. Consider reducing the dose of this drug in these populations to decrease the risk of toxicity .

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.

Description

The antiviral drug valaciclovir is used to treat herpes conditions, including shingles. It is marketed under the trade names Valtrex and Zelitrex and has been sold as a generic since 2009.



Valaciclovir is actually a prodrug; after it is taken orally, it is converted by esterase enzymes to the active drug aciclovir, a viral DNA polymerase inhibitor. Valaciclovir’s advantage is that it is more bioavailable than aciclovir.

Chemical properties

White Solid

Originator

Valcivir,Cipla Limited

The Uses of Valaciclovir

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.

Background

Valaciclovir (valacyclovir), also known as Valtrex, is an antiviral drug that has been used to manage and treat various herpes infections for more than 2 decades. It was initially approved by the FDA in 1995 and marketed by GlaxoSmithKline . Valacyclovir is the L-valine ester of aciclovir. It is a member of the purine (guanine) nucleoside analog drug class . This class of drugs forms an important part of hepatitis, HIV, and cytomegalovirus drug regimens .
One major use of valacyclovir is the treatment of genital herpes episodes or outbreaks. Genital herpes is a frequently diagnosed sexually transmitted disease which currently affects more than 400 million individuals worldwide. It is caused by infection with the herpes simplex virus (HSV). Infection with this virus is lifelong with periodic episodes of reactivation .

Indications

Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for :
Adults
? Cold Sores (Herpes Labialis)
? Genital Herpes
? Treatment of genital herpes lesions in immunocompetent patients (initial or recurrent episode)
? Suppression of genital herpes lesions in immunocompetent or HIV-infected patients
? Reduction of viral transmission
? Herpes Zoster
Pediatric Patients
? Cold Sores (Herpes Labialis)
? Chickenpox
Limitations of use
The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients.

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].

Pharmacokinetics

Antiviral effects
Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors .
Clinical study results
For the various conditions below, clinical study results are summarized as follows :
Cold sores
Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration .
Initial genital herpes episodes
643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days.
Recurrent genital herpes episodes
The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding . These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration.
A note on resistance
The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases .

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

Metabolism

Valacyclovir is converted to acyclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Acyclovir is also transformed, to a small extent, to inactive metabolites by aldehyde oxidase in addition to alcohol dehydrogenase and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes .

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.