Etravirine

Identification

Summary

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infections in combination with other antiretroviral agents.

Brand Names
Intelence
Generic Name
Etravirine
DrugBank Accession Number
DB06414
Background

Etravirine is an antiretroviral agent more specifically classified as a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI). Etraverine is used clinically for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. On January 18, 2007, the FDA granted accelerated approved for the use of etravirine 100mg tablets in the treatment of adult HIV-1 infection documented to be resistant to therapy with other NNRTIs and antiretroviral agents. On March 26, 2012, approval was extended for use in treatment-experienced pediatric patients 6 to 18 years of age, weighing at least 16 kg. Etravarine must always be used in combination with other antiretroviral drugs.

Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1), and consequently blocks DNA-dependent and RNA-dependent polymerase activity. Etravirine does not inhibit human DNA polymerase alpha, beta or gamma.

Common side effects of use include mild to moderate rash within the first 6 weeks of therapy, nausea, diarrhea and peripheral neuropathy. Patients are advised to immediately contact their healthcare provider if a rash develops.

In 2009, postmarketing case reports of Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme, and other hypersensitivity reactions lead to a revision of etravirine's "Warnings and Precautions," as well as notification of health care providers.

In 2013, reports of Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) in the setting of immune reconstitution, as well as more in depth information about the development of rashes in patients taking etravirine, lead to a modification of etravirine's monograph.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 435.277
Monoisotopic: 434.049071779
Chemical Formula
C20H15BrN6O
Synonyms
  • Etravirina
  • Etravirine
External IDs
  • R-165335
  • R165335
  • TMC 125
  • TMC-125
  • TMC125

Pharmacology

Indication

Etravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced patients ≥2 years of age.1

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofHuman immunodeficiency virus type 1 (hiv-1) infection••••••••••••••••••••• •••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Clinical trials have shown no prolongation of QT intervals on electrocardiograms after 8 days of dosing.

Mechanism of action

Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1). It directly binds reverse transcriptase and consequently blocks DNA-dependent and RNA-dependent polymerase activity. Etravirine does not inhibit human DNA polymerase alpha, beta or gamma.

TargetActionsOrganism
UGag-Pol polyproteinNot Available
UGag-Pol polyproteinNot Available
UReverse transcriptase/RNaseH
inhibitor
Human immunodeficiency virus 1
Absorption

Maximum oral absorption is achieved in 2.5-4 hours.

Absorption is unaffected by the concomitant use of oral ranitidine or omeprazole, which decrease gastric acidity.

Administration under fasting conditions resulted in a near 50% decrease in systemic exposure (AUC) when compared to administration after a meal.

Volume of distribution

Distribution of etravirine into compartments other than plasma has not been evaluated in humans.

Protein binding

Plasma protein binding is about 99.9% in vitro. In vitro, 99.6% is bound to albumin, and 97.66% - 99.02% is bound to 1-alpha glycoprotein.

Metabolism

Metabolized (in vitro) by the liver CYP450 enzymes: CYP3A4, CYP2C9, CYP2C19. The major metabolites formed by a methyl hydroxylation of the dimethylbenzonitrile moiety retained less than 90% of etravirine's activity.

Route of elimination

After a 800mg dose of radio-labelled etraverine, 93.7% was found to undergo fecal elimination, with 81.2% - 86.4% eliminated unchanged. 1.2% of the dose was renally eliminated, changed.

Etravirine is dialyzable (hemodialysis).

Half-life

Half life of 9.05-41 hours.

Clearance

Renal clearance of etravirine is negligible (<1.2%), thus no dose adjustments are required in patients with renal impairment.

Clearance is shown to be reduced in patients with Hepatitis B and/or co-infection, however, the safety profile of etravirine does not call for dosage adjustments.

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Etravirine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Etravirine can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Etravirine.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Etravirine.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Etravirine.
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of etravirine, which may increase its serum concentration.
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of etravirine and may reduce its serum concentration.
  • Take after a meal. Take after meals. This increases the bioavailability of etravirine.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IntelenceTablet100 mgOralJanssen Pharmaceuticals2008-03-27Not applicableCanada flag
IntelenceTablet100 mg/1OralJanssen Products LP2008-01-18Not applicableUS flag
IntelenceTablet100 mg/1OralA-S Medication Solutions2008-01-18Not applicableUS flag
IntelenceTablet25 mgOralJanssen Cilag International Nv2016-09-08Not applicableEU flag
IntelenceTablet100 mg/1OralState of Florida DOH Central Pharmacy2009-07-01Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EtravirineTablet200 mg/1OralCarnegie Pharmaceuticals LLC2022-06-07Not applicableUS flag
EtravirineTablet100 mg/1OralLeading Pharma, Llc2022-06-05Not applicableUS flag
EtravirineTablet25 mg/1OralAmneal Pharmaceuticals NY LLC2021-06-14Not applicableUS flag
EtravirineTablet25 mg/1OralAmneal Pharmaceuticals NY LLC2021-06-14Not applicableUS flag
EtravirineTablet200 mg/1OralAvKARE2022-10-04Not applicableUS flag

Categories

ATC Codes
J05AG04 — Etravirine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Aniline and substituted anilines / Benzonitriles / Phenol ethers / Phenoxy compounds / m-Xylenes / Halopyrimidines / Aminopyrimidines and derivatives / Imidolactams / Aryl bromides / Heteroaromatic compounds
show 7 more
Substituents
Amine / Aminopyrimidine / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Aryl bromide / Aryl halide / Azacycle / Benzenoid / Benzonitrile / Carbonitrile
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organobromine compound, aromatic ether, aminopyrimidine, dinitrile (CHEBI:63589)
Affected organisms
Not Available

Chemical Identifiers

UNII
0C50HW4FO1
CAS number
269055-15-4
InChI Key
PYGWGZALEOIKDF-UHFFFAOYSA-N
InChI
InChI=1S/C20H15BrN6O/c1-11-7-14(10-23)8-12(2)17(11)28-19-16(21)18(24)26-20(27-19)25-15-5-3-13(9-22)4-6-15/h3-8H,1-2H3,(H3,24,25,26,27)
IUPAC Name
4-({6-amino-5-bromo-2-[(4-cyanophenyl)amino]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile
SMILES
CC1=CC(=CC(C)=C1OC1=C(Br)C(N)=NC(NC2=CC=C(C=C2)C#N)=N1)C#N

References

General References
  1. FDA Approved Drug Products: Intelence (etravirine) tablets for oral use [Link]
KEGG Drug
D04112
PubChem Compound
193962
PubChem Substance
175427070
ChemSpider
168313
BindingDB
50103642
RxNav
475969
ChEBI
63589
ChEMBL
CHEMBL308954
ZINC
ZINC000000602632
PharmGKB
PA166014703
PDBe Ligand
65B
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Etravirine
PDB Entries
1sv5 / 3m8p
FDA label
Download (642 KB)
MSDS
Download (122 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
TabletOral100 mg
TabletOral100 mg/1
TabletOral200 mg/1
TabletOral25 mg/1
TabletOral25 mg
TabletOral25.00 mg
TabletOral200 mg/tablet
TabletOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2651665No2010-04-272027-06-06Canada flag
CA2350801No2008-05-202019-09-24Canada flag
US6878717Yes2005-04-122020-05-05US flag
US7037917Yes2006-05-022021-06-13US flag
US8003789Yes2011-08-232020-05-01US flag
US7887845Yes2011-02-152019-09-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0169 mg/mLALOGPS
logP3.67ALOGPS
logP5.54Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)10.99Chemaxon
pKa (Strongest Basic)3.49Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area120.64 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity111.87 m3·mol-1Chemaxon
Polarizability41.09 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-014i-0911200000-26b25d818a5bc993076d
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0udj-0910000000-f7b2a59bcc1e1195bf1f
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0udj-0910000000-f7b2a59bcc1e1195bf1f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0101900000-33e354fd9e3dbad9ddb6
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4r-0100900000-da01bbb7f5f5d708476e
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0000900000-13a118ad1dc40b7d5e81
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0000900000-dedc0743ecd7e029472f
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0001900000-aab85e728b561d80d4c4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0100900000-18dc1a349c9d83e2b3bd
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0apl-4209800000-fbc306bb58b0236480e1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-3900000000-02779dd8a02eb6a896f8
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-182.81187
predicted
DeepCCS 1.0 (2019)
[M+H]+185.16988
predicted
DeepCCS 1.0 (2019)
[M+Na]+191.87468
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Not Available
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Gag-Pol polyprotein: Mediates, with Gag polyrotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spher...
Gene Name
gag-pol
Uniprot ID
P03366
Uniprot Name
Gag-Pol polyprotein
Molecular Weight
163287.51 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
Kind
Protein
Organism
Not Available
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Gag-Pol polyprotein: Mediates, with Gag polyrotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spher...
Gene Name
gag-pol
Uniprot ID
P04585
Uniprot Name
Gag-Pol polyprotein
Molecular Weight
162041.05 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72547
Uniprot Name
Reverse transcriptase/RNaseH
Molecular Weight
65223.615 Da
References
  1. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Perez VE, Sanchez-Parra C, Serrano Villar S: [Etravirine drug interactions]. Enferm Infecc Microbiol Clin. 2009 Dec;27 Suppl 2:27-31. doi: 10.1016/S0213-005X(09)73216-1. [Article]
  2. Kakuda TN, Scholler-Gyure M, Hoetelmans RM: Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. doi: 10.2165/11534740-000000000-00000. [Article]
  3. Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. doi: 10.2165/10895940-000000000-00000. [Article]
  4. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  5. Intelence (Etravirine) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Perez VE, Sanchez-Parra C, Serrano Villar S: [Etravirine drug interactions]. Enferm Infecc Microbiol Clin. 2009 Dec;27 Suppl 2:27-31. doi: 10.1016/S0213-005X(09)73216-1. [Article]
  2. Kakuda TN, Scholler-Gyure M, Hoetelmans RM: Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. doi: 10.2165/11534740-000000000-00000. [Article]
  3. Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. doi: 10.2165/10895940-000000000-00000. [Article]
  4. Scholler-Gyure M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, Woodfall B, Hoetelmans RM: A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol. 2008 Oct;66(4):508-16. doi: 10.1111/j.1365-2125.2008.03214.x. Epub 2008 Apr 25. [Article]
  5. Etravirine FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
There is conflicting information in the literature regarding the severity of inhibition of CYP2C19, with some sources suggesting weak inhibition [A15663], some suggesting moderate inhibition [F1510], and some general comments regarding CYP2C19 inhibition [A15662, A15664, A38838].
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Perez VE, Sanchez-Parra C, Serrano Villar S: [Etravirine drug interactions]. Enferm Infecc Microbiol Clin. 2009 Dec;27 Suppl 2:27-31. doi: 10.1016/S0213-005X(09)73216-1. [Article]
  2. Kakuda TN, Scholler-Gyure M, Hoetelmans RM: Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. doi: 10.2165/11534740-000000000-00000. [Article]
  3. Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. doi: 10.2165/10895940-000000000-00000. [Article]
  4. Yanakakis LJ, Bumpus NN: Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metab Dispos. 2012 Apr;40(4):803-14. doi: 10.1124/dmd.111.044404. Epub 2012 Jan 23. [Article]
  5. Viani RM: Role of etravirine in the management of treatment-experienced patients with human immunodeficiency virus type 1. HIV AIDS (Auckl). 2010;2:141-9. Epub 2010 Jun 28. [Article]
  6. Selected Properties of Etravirine, HIVCLINIC.ca [File]

Transporters

Details
1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Kakuda TN, Scholler-Gyure M, Hoetelmans RM: Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. doi: 10.2165/11534740-000000000-00000. [Article]
  2. Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. doi: 10.2165/10895940-000000000-00000. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from ...
Gene Name
ABCB4
Uniprot ID
P21439
Uniprot Name
Phosphatidylcholine translocator ABCB4
Molecular Weight
141521.845 Da
References
  1. Kakuda TN, Scholler-Gyure M, Hoetelmans RM: Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39. doi: 10.2165/11534740-000000000-00000. [Article]
  2. Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. doi: 10.2165/10895940-000000000-00000. [Article]

Drug created at March 19, 2008 16:32 / Updated at March 18, 2024 16:48