Identification

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Name
Valaciclovir
Accession Number
DB00577  (APRD00697)
Type
Small Molecule
Groups
Approved, Investigational
Description

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 [Label] and marketed by GlaxoSmithKline [8]. Valacyclovir is the L-valine ester of aciclovir. It is a member of the purine (guanine) nucleoside analog drug class [9]. This class of drugs forms an important part of hepatitis, HIV, and cytomegalovirus drug regimens [4].

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 [5].

Structure
Thumb
Synonyms
  • L-Valine ester with 9-((2-hydroxyethoxy)methyl)guanine
  • L-Valine, 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)ethyl ester
  • Valaciclovir
  • Valaciclovirum
  • Valacyclovir
External IDs
256 U 87
Product Ingredients
IngredientUNIICASInChI Key
Valaciclovir hydrochlorideG447S0T1VC124832-27-5ZCDDBUOENGJMLV-QRPNPIFTSA-N
Active Moieties
NameKindUNIICASInChI Key
AcyclovirprodrugX4HES1O11F59277-89-3MKUXAQIIEYXACX-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Co ValacyclovirTablet1000 mgOralCobalt LaboratoriesNot applicableNot applicableCanada
Co ValacyclovirTablet500 mgOralCobalt Laboratories2010-07-27Not applicableCanada
Sandoz ValacyclovirTablet500 mgOralSandoz Canada Incorporated2015-07-21Not applicableCanada
Sandoz ValacyclovirTablet1000 mgOralSandoz Canada IncorporatedNot applicableNot applicableCanada
ValacyclovirTablet500 mgOralSorres Pharma IncNot applicableNot applicableCanada
ValacyclovirTablet500 mgOralSivem Pharmaceuticals Ulc2015-10-14Not applicableCanada
ValacyclovirTablet1000 mgOralSivem Pharmaceuticals Ulc2015-10-14Not applicableCanada
ValacyclovirTablet500 mgOralSanis Health Inc2016-06-10Not applicableCanada
ValtrexTablet, film coated1 g/1OralA-S Medication Solutions2002-08-12Not applicableUs54569 532420180907 15195 jakgk3
ValtrexTablet, film coated1 g/1OralA-S Medication Solutions2002-08-12Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-valacyclovirTablet500 mgOralApotex Corporation2008-05-23Not applicableCanada
Apo-valacyclovirTablet1000 mgOralApotex Corporation2011-10-21Not applicableCanada
Auro-valacyclovirTablet500 mgOralAuro Pharma Inc2013-05-30Not applicableCanada
Bio-valacyclovirTablet500 mgOralBiomed Pharma2016-04-07Not applicableCanada
Dom-valacyclovirTablet500 mgOralDominion Pharmacal2010-07-01Not applicableCanada
Ipg-valacyclovirTablet500 mgOralMarcan Pharmaceuticals IncNot applicableNot applicableCanada
Jamp-valacyclovirTablet500 mgOralJamp Pharma Corporation2015-10-14Not applicableCanada
Mar-valacyclovirTablet500 mgOralMarcan Pharmaceuticals Inc2015-10-20Not applicableCanada
Mylan-valacyclovirTablet1000 mgOralMylan Pharmaceuticals2010-05-25Not applicableCanada
Mylan-valacyclovirTablet500 mgOralMylan Pharmaceuticals2010-05-25Not applicableCanada
International/Other Brands
Bagovir (Bago) / Cycloval (GMP) / Mitanga (Aversi) / Ovalac (Beximco) / Pervioral (Royal Pharma) / Revira (Square) / Vacyless (Yung Shin) / Vadiral (Gynopharm) / Valdacir (Actavis) / Valotix (Rowex) / Valvir (Soho) / Valztrex (Northia) / Viramixal (Panalab) / Viropel (Pelpharma) / Vociflon (Pharmathen) / Zelitrex (GlaxoSmithKline) / Zelivire (Ranbaxy)
Categories
UNII
MZ1IW7Q79D
CAS number
124832-26-4
Weight
Average: 324.3357
Monoisotopic: 324.154603158
Chemical Formula
C13H20N6O4
InChI Key
HDOVUKNUBWVHOX-QMMMGPOBSA-N
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
IUPAC Name
2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
SMILES
CC(C)[C@H](N)C(=O)OCCOCN1C=NC2=C1NC(N)=NC2=O

Pharmacology

Indication

Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for [Label]:

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 [Label]

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.

Associated Conditions
Associated Therapies
Pharmacodynamics

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 [Label].

Clinical study results

For the various conditions below, clinical study results are summarized as follows [Label]:

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 [Label].

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 [Label]. 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 [Label].

Mechanism of action

Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir [1].

Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form [9].

The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication [9]. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for thymidine kinase (TK)[Label].

In summary, the antiviral effects of valacyclovir are achieved in 3 ways [Label]:

1) competitive inhibition of viral DNA polymerase

2) incorporation and termination of the growing viral DNA chain

3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK).

TargetActionsOrganism
ADNA polymerase catalytic subunit
inhibitor
HHV-1
AThymidine kinase
substrate
HHV-1
UHerpes simplex virus 1
inhibitor
Human herpesvirus 1
UVaricella Zoster Virus (VZV) (Human herpes virus 3)
inhibitor
Human Herpes Virus
UCytomegalovirus
inhibitor
Human Herpes Virus
UHerpes simplex virus 2
inhibitor
UEpstein-Barr Virus (EBV) (human herpes virus 4)
inhibitor
Human Herpes Virus
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 [Label].

Volume of distribution

Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma AUC ratio, is approximately 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and approximately 2.5% for the metabolite 9-(carboxymethoxy)methylguanine [9].

In a study of immunocompromised pediatric patients, the volume of distribution of a 15 ml/kg dose of valacyclovir was 1.34 ± 0.65 L/kg [6].

Protein binding

The binding of valacyclovir to human plasma proteins is low and ranges from 13.5% to 17.9% [Label].

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 [Label].

Route of elimination

After oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was measured in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine [Label].

Half life

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function [Label].

Clearance

Renal clearance of acyclovir following the administration of a single 1 gram dose of valacylcovir to 12 healthy 437 volunteers was approximately 255 ± 86 mL/min, which represents 42% of total acyclovir apparent plasma clearance [Label].

Toxicity

LD50 Oral

Rat – 903.5 mg/kg [10]

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 [Label].

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 [Label].

Valacyclovir did not impair fertility or reproduction in rats at 6 times the normal concentrations in human plasma [Label].

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 [Label].

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 [Label].

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 [Label].

Affected organisms
  • Humans and other mammals
  • Herpes simplex virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirValaciclovir may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseValaciclovir may decrease the excretion rate of Acarbose which could result in a higher serum level.
AceclofenacValaciclovir may decrease the excretion rate of Aceclofenac which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Valaciclovir which could result in a higher serum level.
AcetaminophenValaciclovir may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Valaciclovir which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Valaciclovir which could result in a higher serum level.
AclidiniumValaciclovir may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineValaciclovir may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirValaciclovir may decrease the excretion rate of Acyclovir which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

Marina Etinger, "Synthesis and purification of valacyclovir." U.S. Patent US20030153757, issued August 14, 2003.

US20030153757
General References
  1. Beutner KR: Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res. 1995 Dec;28(4):281-90. [PubMed:8669888]
  2. Asahi T, Tsutsui M, Wakasugi M, Tange D, Takahashi C, Tokui K, Okazawa S, Okudera H: Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009 Apr;16(4):457-60. doi: 10.1111/j.1468-1331.2008.02527.x. [PubMed:19187258]
  3. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009. [PubMed:9118821]
  4. De Clercq E, Li G: Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 2016 Jul;29(3):695-747. doi: 10.1128/CMR.00102-15. [PubMed:27281742]
  5. Groves MJ: Genital Herpes: A Review. Am Fam Physician. 2016 Jun 1;93(11):928-34. [PubMed:27281837]
  6. Bomgaars L, Thompson P, Berg S, Serabe B, Aleksic A, Blaney S: Valacyclovir and acyclovir pharmacokinetics in immunocompromised children. Pediatr Blood Cancer. 2008 Oct;51(4):504-8. doi: 10.1002/pbc.21638. [PubMed:18561175]
  7. Valacyclovir: AAFP [Link]
  8. Valacyclovir approval package [Link]
  9. Valtrex tablets, MedSafe NZ [File]
  10. Valacyclovir hydrochloride hydrate MSDS [File]
External Links
Human Metabolome Database
HMDB0014716
KEGG Drug
D00398
KEGG Compound
C07184
PubChem Compound
60773
PubChem Substance
46508197
ChemSpider
54770
BindingDB
50162073
ChEBI
35854
ChEMBL
CHEMBL1349
Therapeutic Targets Database
DAP000643
PharmGKB
PA451839
HET
TXC
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Valaciclovir
ATC Codes
J05AB11 — Valaciclovir
AHFS Codes
  • 08:18.32 — Nucleosides and Nucleotides
PDB Entries
4aql / 6gz9
FDA label
Download (185 KB)
MSDS
Download (29.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCancer of the Ovary / Cancer, Breast / Lung Cancers / Malignant Pleural Effusions / Mesothelioma1
1Active Not RecruitingTreatmentEpendymoma, Recurrent / Malignant Gliomas1
1CompletedNot AvailableHealthy Volunteers5
1CompletedNot AvailableHerpes Simplex Virus Infection / Varicella Zoster Virus Infection1
1CompletedTreatmentAdenocarcinoma of the Pancreas / Malignant Neoplasm of Pancreas1
1CompletedTreatmentAnaplastic Astrocytoma (AA) / Glioblastoma Multiforme (GBM) / Malignant Gliomas1
1CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
1CompletedTreatmentHealthy Volunteers3
1CompletedTreatmentHerpes Simplex1
1CompletedTreatmentHerpes Simplex Virus 21
1CompletedTreatmentShingles / Transplantation, Bone Marrow1
1RecruitingTreatmentGlioma, Malignant1
1TerminatedNot AvailableSafety of ASP21511
1Unknown StatusPreventionHerpes Simplex1
1Unknown StatusTreatmentHepatitis C Virus Infection / Herpesvirus 2, Human / Infection NOS1
1WithdrawnTreatmentChickenpox / Herpes Simplex / Human Immunodeficiency Virus (HIV) Infections1
1, 2CompletedTreatmentInfectious Mononucleosis1
1, 2RecruitingTreatmentProstatic Neoplasms1
2Active Not RecruitingBasic ScienceANCA Associated Vasculitis / CMV Infections1
2Active Not RecruitingTreatmentWaldenström's Macroglobulinemia (WM)1
2CompletedPreventionCritical Illness1
2CompletedPreventionHerpes simplex of the genitals / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentAnaplastic Astrocytoma (AA) / Glioblastoma Multiforme (GBM) / Malignant Gliomas1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemias1
2CompletedTreatmentHerpes Labialis1
2CompletedTreatmentHerpes Simplex / Human Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHerpes Zoster2
2CompletedTreatmentHerpes Zoster / Shingles1
2CompletedTreatmentHerpes simplex of the genitals1
2CompletedTreatmentNeoplasms1
2CompletedTreatmentNicotine Dependence1
2CompletedTreatmentPsychosis1
2CompletedTreatmentPsychosis / Schizophrenic Disorders1
2CompletedTreatmentSchizoaffective Disorders / Schizophrenic Disorders1
2CompletedTreatmentSchizophrenic Disorders1
2Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD) / EBV1
2RecruitingPreventionEpstein-Barr Virus Infections / Infections, Cytomegalovirus / Transplantation Infection1
2RecruitingTreatmentAlzheimer's Disease (AD) / Herpes simplex 1 / Herpes Simplex 21
2RecruitingTreatmentAlzheimer's Disease (AD) / Herpes Simplex / Mild Cognitive Impairment (MCI)1
2RecruitingTreatmentHerpetic Gingivostomatitis1
2RecruitingTreatmentHigh-risk Prostate Cancer / Prostate Cancer1
2RecruitingTreatmentLung Squamous Cell Carcinoma Stage IV / Metastatic Uveal Melanoma / Nonsquamous Nonsmall Cell Neoplasm of Lung1
2RecruitingTreatmentMetastatic Non-Small Cell Lung Cancer / Metastatic Triple-negative Breast Cancer1
2TerminatedPreventionGenital Herpes1
2Unknown StatusTreatmentBipolar Disorder (BD)1
2Unknown StatusTreatmentHerpes Zoster / Postherpetic Neuralgia1
2, 3RecruitingPreventionCytomegalovirus Congenital Infection1
2, 3RecruitingTreatmentProstate Cancer1
3CompletedPreventionHerpes Simplex / Human Immunodeficiency Virus (HIV) Infections / Sexually Transmitted Disease (STD)2
3CompletedSupportive CareMalignancies1
3CompletedTreatmentGenital Herpes1
3CompletedTreatmentHerpes Simplex1
3CompletedTreatmentHerpes Simplex Type II / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHerpes Simplex / Human Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHerpes Zoster1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infections, Cytomegalovirus1
3CompletedTreatmentInflammation, Brain1
3RecruitingTreatmentProstate Cancer1
3TerminatedPreventionHerpes Zoster / Postherpetic Neuralgia / Shingles1
3Unknown StatusTreatmentHerpes Simplex / Herpes simplex of the genitals / Human Immunodeficiency Virus (HIV) Infections1
4CompletedNot AvailableHerpes Simplex Virus Infection / Varicella Zoster Virus Infection1
4CompletedPreventionHerpes Simplex / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentBell's Palsy1
4CompletedTreatmentGenital Herpes2
4CompletedTreatmentGenital Herpes / Herpes Labialis1
4CompletedTreatmentGenital Herpes / Herpes simplex of the genitals1
4CompletedTreatmentGenital Herpes / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentGenital Herpes / Infections, Herpesviridae1
4CompletedTreatmentHerpes Simplex Infection / Human Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentVirus Diseases1
4RecruitingTreatmentVaricella-zoster virus acute retinal necrosis1
4TerminatedNot AvailableGenital Herpes / Human Immunodeficiency Virus (HIV) Infections1
4TerminatedTreatmentInfections, Cytomegalovirus / Viral Diseases1
Not AvailableCompletedNot AvailableHealthy Volunteers2
Not AvailableCompletedNot AvailableVaricella1
Not AvailableCompletedPreventionHerpes Simplex Type Two Infection / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentAcne Scars - Mixed Atrophic and Hypertrophic1
Not AvailableCompletedTreatmentBell's Palsy1
Not AvailableCompletedTreatmentGenital Herpes / Herpes Zoster / Shingles2
Not AvailableCompletedTreatmentHSV-2 / Human Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentHerpes Simplex / Human Immunodeficiency Virus (HIV) Infections3
Not AvailableCompletedTreatmentHerpes Zoster / Immunologic Deficiency Syndromes1
Not AvailableCompletedTreatmentHerpes Zoster / Post-Herpetic Neuralgia (PHN)1
Not AvailableWithdrawnBasic ScienceHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableWithdrawnPreventionBacterial Vaginosis (BV) / Herpes Simplex Virus Type II1

Pharmacoeconomics

Manufacturers
  • Aurobindo pharma ltd
  • Dr reddys laboratories ltd
  • Matrix laboratories ltd
  • Mylan pharmaceuticals inc
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
  • Wockhardt ltd
  • Glaxosmithkline
Packagers
  • Apotheca Inc.
  • A-S Medication Solutions LLC
  • Aurobindo Pharma Ltd.
  • Bryant Ranch Prepack
  • Cardinal Health
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • DSM Corp.
  • GlaxoSmithKline Inc.
  • Greenstone LLC
  • Kaiser Foundation Hospital
  • Lake Erie Medical and Surgical Supply
  • Long Wing International Inc.
  • Lupin Pharmaceuticals Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • PD-Rx Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Promex Medical Inc.
  • Ranbaxy Laboratories
  • Redpharm Drug
  • Resource Optimization and Innovation LLC
  • Roxane Labs
  • Sandoz
  • Southwood Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • Tya Pharmaceuticals
  • Watson Pharmaceuticals
  • Wockhardt Ltd.
Dosage forms
FormRouteStrength
TabletOral1000 mg
CapsuleOral1 g/1
Tablet, film coatedOral1000 mg/1
TabletOral1 g/1
TabletOral1000 mg/1
TabletOral500 mg/1
Tablet, coatedOral500 mg/1
Tablet, film coatedOral1 g/1
Tablet, film coatedOral500 mg/1
TabletOral500 mg
Prices
Unit descriptionCostUnit
Valtrex 1 gm tablet14.62USD tablet
Valtrex 1 gm caplet14.06USD caplet
Valacyclovir HCl 1 gm tablet12.87USD tablet
Valtrex 500 mg tablet8.36USD tablet
Valacyclovir HCl 500 mg tablet7.35USD tablet
Valtrex (Caplet) 500 mg Tablet3.82USD tablet
Apo-Valacyclovir (Caplet) 500 mg Tablet2.14USD tablet
Pms-Valacyclovir (Caplet) 500 mg Tablet2.14USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4957924No1990-09-182009-12-23Us
CA2243237No2008-09-022017-01-17Canada
CA1340083No1998-10-132015-10-13Canada
US5879706Yes1999-03-092016-07-19Us
US6107302Yes2000-08-222016-07-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)170-172https://www.chemicalbook.com/ChemicalProductProperty_US_CB8430566.aspx
water solubility174 mg/mL at 25 degrees Celsiushttps://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020487s007rel2_lbl.pdf
logP-0.3https://pubchem.ncbi.nlm.nih.gov/compound/valacyclovir#section=Vapor-Density
pKa1.90, 7.47, and 9.43https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020487s007rel2_lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility3.55 mg/mLALOGPS
logP-0.84ALOGPS
logP-0.45ChemAxon
logS-2ALOGPS
pKa (Strongest Acidic)8.1ChemAxon
pKa (Strongest Basic)7.36ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area146.85 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity80.63 m3·mol-1ChemAxon
Polarizability31.96 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9475
Blood Brain Barrier+0.9389
Caco-2 permeable-0.8957
P-glycoprotein substrateSubstrate0.7487
P-glycoprotein inhibitor INon-inhibitor0.7467
P-glycoprotein inhibitor IINon-inhibitor0.9586
Renal organic cation transporterNon-inhibitor0.8553
CYP450 2C9 substrateNon-substrate0.8941
CYP450 2D6 substrateNon-substrate0.8244
CYP450 3A4 substrateSubstrate0.5571
CYP450 1A2 substrateNon-inhibitor0.8155
CYP450 2C9 inhibitorNon-inhibitor0.8734
CYP450 2D6 inhibitorNon-inhibitor0.8797
CYP450 2C19 inhibitorNon-inhibitor0.7944
CYP450 3A4 inhibitorNon-inhibitor0.9351
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8373
Ames testNon AMES toxic0.6139
CarcinogenicityNon-carcinogens0.9345
BiodegradationNot ready biodegradable0.899
Rat acute toxicity2.2217 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9427
hERG inhibition (predictor II)Non-inhibitor0.7378
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-1910000000-3db14f76ba496cea0d81

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid esters
Alternative Parents
Valine and derivatives / 6-oxopurines / Hypoxanthines / Pyrimidones / Aminopyrimidines and derivatives / Fatty acid esters / N-substituted imidazoles / Vinylogous amides / Heteroaromatic compounds / Carboxylic acid esters
show 7 more
Substituents
Alpha-amino acid ester / Valine or derivatives / 6-oxopurine / Hypoxanthine / Imidazopyrimidine / Purine / Aminopyrimidine / Pyrimidone / Fatty acid ester / N-substituted imidazole
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
L-valinyl ester (CHEBI:35854)

Targets

Kind
Protein
Organism
HHV-1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding pro...
Gene Name
Not Available
Uniprot ID
P04293
Uniprot Name
DNA polymerase catalytic subunit
Molecular Weight
136419.66 Da
References
  1. Scott GM, Ng HL, Morton CJ, Parker MW, Rawlinson WD: Murine cytomegalovirus resistant to antivirals has genetic correlates with human cytomegalovirus. J Gen Virol. 2005 Aug;86(Pt 8):2141-51. [PubMed:16033961]
  2. Huang L, Ishii KK, Zuccola H, Gehring AM, Hwang CB, Hogle J, Coen DM: The enzymological basis for resistance of herpesvirus DNA polymerase mutants to acyclovir: relationship to the structure of alpha-like DNA polymerases. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):447-52. [PubMed:9892653]
  3. Drug information, Valacyclovir [File]
  4. Valtrex FDA label [File]
Kind
Protein
Organism
HHV-1
Pharmacological action
Yes
Actions
Substrate
General Function
Thymidine kinase activity
Specific Function
In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate the...
Gene Name
TK
Uniprot ID
Q9QNF7
Uniprot Name
Thymidine kinase
Molecular Weight
40896.475 Da
References
  1. Sergerie Y, Boivin G: Thymidine kinase mutations conferring acyclovir resistance in herpes simplex type 1 recombinant viruses. Antimicrob Agents Chemother. 2006 Nov;50(11):3889-92. doi: 10.1128/AAC.00889-06. Epub 2006 Sep 18. [PubMed:16982796]
  2. FDA label, Valtrex [File]
  3. Valtrex tablets, MedSafe NZ [File]
3. Herpes simplex virus 1
Kind
Organism
Organism
Human herpesvirus 1
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009. [PubMed:9118821]
  2. Valacyclovir FDA label [File]
  3. Valtrex tablets, MedSafe NZ [File]
4. Varicella Zoster Virus (VZV) (Human herpes virus 3)
Kind
Organism
Organism
Human Herpes Virus
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009. [PubMed:9118821]
  2. Valtrex tablets, MedSafe NZ [File]
5. Cytomegalovirus
Kind
Organism
Organism
Human Herpes Virus
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Ong SY, Truong HT, Diong CP, Linn YC, Ho AY, Goh YT, Hwang WY: Use of Valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation. BMC Hematol. 2015 Jun 19;15:8. doi: 10.1186/s12878-015-0028-2. eCollection 2015. [PubMed:26090121]
  2. Kervan U, Kucuker SA, Kocabeyoglu SS, Unal EU, Ozatik MA, Sert DE, Kavasoglu K, Tezer AY, Pac M: Low-Dose Valacyclovir for Cytomegalovirus Infection Prophylaxis After a Heart Transplant. Exp Clin Transplant. 2016 Oct;14(5):551-554. doi: 10.6002/ect.2015.0109. Epub 2016 Mar 14. [PubMed:26976362]
  3. Valtrex tablets, MedSafe NZ [File]
6. Herpes simplex virus 2
Kind
Organism
Organism
Not Available
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009. [PubMed:9118821]
  2. Valtrex tablets, MedSafe NZ [File]
7. Epstein-Barr Virus (EBV) (human herpes virus 4)
Kind
Organism
Organism
Human Herpes Virus
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Valtrex tablets, MedSafe NZ [File]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Guanylate kinase activity
Specific Function
Essential for recycling GMP and indirectly, cGMP.
Gene Name
GUK1
Uniprot ID
Q16774
Uniprot Name
Guanylate kinase
Molecular Weight
21725.41 Da
References
  1. Ardiani A, Goyke A, Black ME: Mutations at serine 37 in mouse guanylate kinase confer resistance to 6-thioguanine. Protein Eng Des Sel. 2009 Apr;22(4):225-32. doi: 10.1093/protein/gzn078. Epub 2009 Jan 10. [PubMed:19136674]
  2. FDA label Valacyclovir [File]
Kind
Protein
Organism
Not Available
Pharmacological action
Unknown
Actions
Substrate
General Function
Thymidine kinase activity
Specific Function
In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate the...
Gene Name
TK
Uniprot ID
P06478
Uniprot Name
Thymidine kinase
Molecular Weight
40912.485 Da
References
  1. Beutner KR: Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res. 1995 Dec;28(4):281-90. [PubMed:8669888]
  2. Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009. [PubMed:9118821]
  3. FDA label Valacyclovir [File]
  4. Valtrex tablets, MedSafe NZ [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH: Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998 May 19;246(2):470-5. [PubMed:9610386]
  2. Han H, de Vrueh RL, Rhie JK, Covitz KM, Smith PL, Lee CP, Oh DM, Sadee W, Amidon GL: 5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 1998 Aug;15(8):1154-9. [PubMed:9706043]
  3. Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH, Tsuji A, Sinko PJ: Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophys Res Commun. 1998 Sep 18;250(2):246-51. [PubMed:9753615]
  4. Sawada K, Terada T, Saito H, Hashimoto Y, Inui KI: Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J Pharmacol Exp Ther. 1999 Nov;291(2):705-9. [PubMed:10525090]
  5. Balimane P, Sinko P: Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepT1) in CHO cells. Biopharm Drug Dispos. 2000 Jul;21(5):165-74. [PubMed:11180195]
  6. Guo A, Hu P, Balimane PV, Leibach FH, Sinko PJ: Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line. J Pharmacol Exp Ther. 1999 Apr;289(1):448-54. [PubMed:10087037]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Peptide:proton symporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
Gene Name
SLC15A2
Uniprot ID
Q16348
Uniprot Name
Solute carrier family 15 member 2
Molecular Weight
81782.77 Da
References
  1. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH: Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998 May 19;246(2):470-5. [PubMed:9610386]
  2. Sawada K, Terada T, Saito H, Hashimoto Y, Inui KI: Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J Pharmacol Exp Ther. 1999 Nov;291(2):705-9. [PubMed:10525090]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Endou H: Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24. [PubMed:11861798]
  2. Mooij MG, Nies AT, Knibbe CA, Schaeffeler E, Tibboel D, Schwab M, de Wildt SN: Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics. Clin Pharmacokinet. 2016 May;55(5):507-24. doi: 10.1007/s40262-015-0328-5. [PubMed:26410689]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H: Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9. [PubMed:10945832]
  2. Mooij MG, Nies AT, Knibbe CA, Schaeffeler E, Tibboel D, Schwab M, de Wildt SN: Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics. Clin Pharmacokinet. 2016 May;55(5):507-24. doi: 10.1007/s40262-015-0328-5. [PubMed:26410689]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Neurotransmitter:sodium symporter activity
Specific Function
Mediates the uptake of a broad range of neutral and cationic amino acids (with the exception of proline) in a Na(+)/Cl(-)-dependent manner.
Gene Name
SLC6A14
Uniprot ID
Q9UN76
Uniprot Name
Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+)
Molecular Weight
72152.145 Da
References
  1. Umapathy NS, Ganapathy V, Ganapathy ME: Transport of amino acid esters and the amino-acid-based prodrug valganciclovir by the amino acid transporter ATB(0,+). Pharm Res. 2004 Jul;21(7):1303-10. [PubMed:15290873]
  2. Yang B, Smith DE: Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice. Drug Metab Dispos. 2013 Mar;41(3):608-14. doi: 10.1124/dmd.112.049239. Epub 2012 Dec 21. [PubMed:23264448]
  3. Hatanaka T, Haramura M, Fei YJ, Miyauchi S, Bridges CC, Ganapathy PS, Smith SB, Ganapathy V, Ganapathy ME: Transport of amino acid-based prodrugs by the Na+- and Cl(-) -coupled amino acid transporter ATB0,+ and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther. 2004 Mar;308(3):1138-47. doi: 10.1124/jpet.103.057109. Epub 2003 Nov 14. [PubMed:14617696]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Bile acid:sodium symporter activity
Specific Function
Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism.
Gene Name
SLC10A2
Uniprot ID
Q12908
Uniprot Name
Ileal sodium/bile acid cotransporter
Molecular Weight
37713.405 Da
References
  1. Tolle-Sander S, Lentz KA, Maeda DY, Coop A, Polli JE: Increased acyclovir oral bioavailability via a bile acid conjugate. Mol Pharm. 2004 Jan 12;1(1):40-8. [PubMed:15832499]
  2. Dawson PA: Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol. 2011;(201):169-203. doi: 10.1007/978-3-642-14541-4_4. [PubMed:21103970]
  3. Rais R, Acharya C, Tririya G, Mackerell AD, Polli JE: Molecular switch controlling the binding of anionic bile acid conjugates to human apical sodium-dependent bile acid transporter. J Med Chem. 2010 Jun 24;53(12):4749-60. doi: 10.1021/jm1003683. [PubMed:20504026]

Drug created on June 13, 2005 07:24 / Updated on April 18, 2019 06:15