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Identification
NameEfavirenz
Accession NumberDB00625  (APRD00059, DB07709)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Efavirenz (brand names Sustiva® and Stocrin®) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

For HIV infection that has not previously been treated, efavirenz and lamivudine in combination with zidovudine or tenofovir is the preferred NNRTI-based regimen.

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission.

Structure
Thumb
Synonyms
SynonymLanguageCode
(-)-6-CHLORO-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneNot AvailableNot Available
(S)-6-chloro-4-(Cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-oneNot AvailableNot Available
(S)-6-chloro-4-Cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-benzo[D][1,3]oxazin-2-oneNot AvailableNot Available
6-chloro-4-(2-Cyclopropyl-1-ethynyl)-4-trifluoromethyl-(4S)-1,4-dihydro-2H-benzo[D][1,3]oxazin-2-oneNot AvailableNot Available
EfavirenzGerman/SpanishINN
ÉfavirenzFrenchINN
EfavirenzumLatinINN
SaltsNot Available
Brand names
NameCompany
E.FMcNeil & Argus
EfavirCipla
EfavirenzAspen Pharmacare
EfcureEmcure Pharmaceuticals
EffervenRanbaxy Laboratories
EstivaHetero
EvirenzAlkem Laboratories
StocrinMerck & Co.
SustivaBristol-Myers Squibb
ViranzAurobindo Pharma
Brand mixturesNot Available
Categories
CAS number154598-52-4
WeightAverage: 315.675
Monoisotopic: 315.027390859
Chemical FormulaC14H9ClF3NO2
InChI KeyXPOQHMRABVBWPR-ZDUSSCGKSA-N
InChI
InChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1
IUPAC Name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
SMILES
FC(F)(F)[C@]1(OC(=O)NC2=C1C=C(Cl)C=C2)C#CC1CC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzoxazines
SubclassNot Available
Direct parentBenzoxazines
Alternative parentsChlorobenzenes; Aryl Chlorides; Ynones; Carbamic Acids and Derivatives; Polyamines; Organochlorides; Organofluorides; Alkyl Fluorides
Substituentschlorobenzene; aryl chloride; ynone; benzene; aryl halide; carbamic acid derivative; polyamine; organohalogen; organochloride; organofluoride; organonitrogen compound; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the benzoxazines. These are organic compounds containing a benzene fused to an oxazine ring (a six-member aliphatic ring with four carbon atoms, one oxygen atom, and one nitrogen atom).
Pharmacology
IndicationFor use in combination treatment of HIV infection (AIDS)
PharmacodynamicsEfavirenz (dideoxyinosine, ddI) is an oral nucleoside reverse transcriptase inhibitor (NRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.
Mechanism of actionSimilar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding99.5-99.75%
Metabolism

Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1.

Route of eliminationNearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.
Half life40-55 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Human Immunodeficiency Virus
Pathways
PathwayCategorySMPDB ID
Efavirenz Action PathwayDrug actionSMP00740
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9964
Blood Brain Barrier + 0.9182
Caco-2 permeable + 0.5553
P-glycoprotein substrate Non-substrate 0.7617
P-glycoprotein inhibitor I Non-inhibitor 0.7451
P-glycoprotein inhibitor II Non-inhibitor 0.9557
Renal organic cation transporter Non-inhibitor 0.9157
CYP450 2C9 substrate Non-substrate 0.8033
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6037
CYP450 1A2 substrate Inhibitor 0.6996
CYP450 2C9 substrate Non-inhibitor 0.6975
CYP450 2D6 substrate Non-inhibitor 0.8699
CYP450 2C19 substrate Non-inhibitor 0.5291
CYP450 3A4 substrate Non-inhibitor 0.7577
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6705
Ames test Non AMES toxic 0.6991
Carcinogenicity Non-carcinogens 0.8997
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5416 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9617
hERG inhibition (predictor II) Non-inhibitor 0.9098
Pharmacoeconomics
Manufacturers
  • Bristol myers squibb co
  • Bristol myers squibb pharma co
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
TabletOral
Prices
Unit descriptionCostUnit
Sustiva 600 mg tablet21.68USDtablet
Sustiva 200 mg capsule7.37USDcapsule
Sustiva 100 mg capsule3.34USDcapsule
Sustiva 50 mg capsule1.84USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States62386951999-04-062019-04-06
United States58114231992-08-072012-08-07
Canada22791982009-04-142018-02-02
Canada21015722001-08-282013-07-29
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point139-141 °CNot Available
logP4.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00855ALOGPS
logP3.89ALOGPS
logP4.46ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)12.52ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.33 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity71.34 m3·mol-1ChemAxon
Polarizability26.81 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

John Doney, “Amorphous efavirenz and the production thereof.” U.S. Patent US20070026073, issued February 01, 2007.

US20070026073
General Reference
  1. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK: Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14410-5. Epub 2002 Oct 17. Pubmed
External Links
ResourceLink
KEGG DrugD00896
KEGG CompoundC08088
PubChem Compound64139
PubChem Substance46506827
ChemSpider57715
BindingDB2483
ChEBI119486
ChEMBLCHEMBL223228
Therapeutic Targets DatabaseDAP000709
PharmGKBPA449441
HETEFZ
Drug Product Database2246045
RxListhttp://www.rxlist.com/cgi/generic/efaviren.htm
Drugs.comhttp://www.drugs.com/cdi/efavirenz.html
WikipediaEfavirenz
ATC CodesJ05AG03
AHFS Codes
  • 08:18.08.16
PDB EntriesNot Available
FDA labelshow(154 KB)
MSDSshow(57.6 KB)
Interactions
Drug Interactions
Drug
AlprazolamThe antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, alprazolam.
AstemizoleIncreased risk of cardiotoxicity and arrhythmias
AtazanavirEfavirenz decreases the levels/effects of atazanavir
AtorvastatinEfavirenz may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if efavirenz is initiated, discontinued or dose changed.
CisaprideIncreased risk of cardiotoxicity and arrhythmias
ClarithromycinEfavirenz decreases levels of clarithromycin
CyclosporineEfavirenz decreases the levels of cyclosporine
DihydroergotamineEfavirenze may increase the adverse/toxic effects of dihydroergotamine. Concomitant therapy is contraindicated.
EltrombopagAffects hepatic enzyme CYP2C9/10 metabolism and may increase the level of eltrombopag.
ErgotamineThe antiretroviral agent may increase the ergot derivative toxicity
Estradiol valerate/DienogestAffects CYP3A4 metabolism, decreases or effects levels of Estradiol valerate/Dienogest.
EtravirineEtravirine, when used concomitantly with Efavirenz, may experience a significant decrease in plasma levels and a loss of efficacy. Combination of two NNRTIs has not been demonstrated to be of benefit to HIV therapy. It is recommended to avoid this combination.
IndinavirEfavirenz decreases the effect of indinavir
LovastatinEfavirenz may decrease the serum concentration of lovastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if efavirenz is initiated, discontinued or dose changed.
MethadoneEfavirenz may decrease the serum concentration of methadone by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of methadone if efavirenz is initiated, discontinued or dose changed.
MethylergometrineThe antiretroviral agent may increase the ergot derivative toxicity
MethysergideThe antiretroviral agent may increase the ergot derivative toxicity
MidazolamThe antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, midazolam.
RilpivirineConcentration of rilpivirine decreases by affecting CYP3A4 metabolism. Concomitant use is contraindicated. Rilpivirine should not be used with other NNRTI's.
RoflumilastAffects CYP3A4 metabolism, decreases level or effect of roflumilast.
SaquinavirEfavirenz decreases the effect of saquinavir
SimvastatinEfavirenz may decrease the serum concentration of simvastatin. Monitor for changes in the therapeutic and adverse effects of simvastatin if efavirenz is initiated, discontinued or dose changed.
St. John's WortSt. John's Wort decreases the antiretroviral effect
TamsulosinEfavirenz, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Efavirenz is initiated, discontinued, or dose changed.
TelaprevirInducers of CYP3A enzymes will decrease telaprevir levels.
TelithromycinEfavirenz may decrease the plasma concentration of Telithromycin. Consider alternate therapy.
TemsirolimusEfavirenz may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
TerfenadineIncreased risk of cardiotoxicity and arrhythmias
TipranavirEfavirenz may alter the serum concentration Tipranavir. Monitor for changes in Tipranavir therapeutic and adverse effects if Efavirenz is initiated, discontinued or dose changed.
TolterodineEfavirenz may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.
TramadolEfavirenz may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
TrazodoneThe CYP3A4 inhibitor and inducer, Efavirenz, may alter Trazodone efficacy/toxicity by altering Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Efavirenz is initiated, discontinued or dose changed.
TriazolamThe antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, triazolam.
VandetanibDecreases levels of vandetanib by affecting CYP3A4 metabolism. Contraindicated.
VoriconazoleEfavirenze may decrease the serum concentration of voriconazole likely by increasing its metabolism. Voriconazole may increase the serum concentration of efavirenz by decreasing its metabolism. Consider alternate therapy or adjust doses and monitor for reduced voriconazole efficacy and increased efavirenz adverse effects during concomitant therapy.
Food Interactions
  • Avoid excessive or chronic alcohol consumption.
  • Take without regard to meals.

Targets

1. Reverse Transcriptase

Kind: protein

Organism: Human immunodeficiency virus 1

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Reverse transcriptase/RNaseH Q72547 Details

References:

  1. Gazzard BG: Efavirenz in the management of HIV infection. Int J Clin Pract. 1999 Jan-Feb;53(1):60-4. Pubmed
  2. Adkins JC, Noble S: Efavirenz. Drugs. 1998 Dec;56(6):1055-64; discussion 1065-6. Pubmed

Enzymes

1. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Hesse LM, von Moltke LL, Shader RI, Greenblatt DJ: Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos. 2001 Feb;29(2):100-2. Pubmed
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  4. Walsky RL, Astuccio AV, Obach RS: Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 2006 Dec;46(12):1426-38. Pubmed
  5. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11