Identification

Name
Enzalutamide
Accession Number
DB08899
Description

Enzalutamide is an androgen receptor inhibitor for the treatment of castration-resistant prostate cancer. FDA approved on August 31, 2012.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 464.436
Monoisotopic: 464.093009286
Chemical Formula
C21H16F4N4O2S
Synonyms
  • Enzalutamida
  • Enzalutamide
External IDs
  • MDV 3100
  • MDV-3100
  • MDV3100

Pharmacology

Indication

Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Resitance to enzalutamide therapy has been observed. This may occurred due to an upregulation of NF-κB2/p52.

Mechanism of action

Enzalutamide is a competitive androgen receptor inhibitor that effects multiple stages of the signalling pathway. It is able to inhibit androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with DNA. As a result, proliferation of prostate cancer cells decreases which ultimately leads to apoptosis and decreased tumour volume.

TargetActionsOrganism
AAndrogen receptor
inhibitor
Humans
Absorption

The pharmacokinetic profile of enzalutamide and N-desmethyl enzalutamide (its major active metabolite) is described by a linear two-compartment model with first-order absorption. Enzalutamide also accumulates. Food does not affect its absorption. Tmax, prostate cancer patients = 1 hour (range of 0.5-3 hours); Cmax, steady state, enzalutamide = 16.6 μg/mL; Cmax, steady state, N-desmethyl enzalutamide = 12.7 μg/mL; Time to steady state, daily dosing = 28 days;

Volume of distribution

Apparent volume of distribution (Vd/F), single oral dose = 110 L

Protein binding

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins.

Metabolism

Enzalutamide is hepatically metabolized, primarily by CYP2C8 and CYP3A4. The enzyme that converts enzalutamide to its active metabolite, N-desmethyl enzalutamide, is CYP2C8. The activity of N-desmethyl-enzalutamide is similar to that of the parent compound.

Route of elimination

Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

Half-life

The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Clearance

Apparent clearance (CL/F), single oral dose = 0.56 L/h (range of 0.33 - 1.02 L/h)

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Affected organisms
  • Humans and other mammals
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
AbacavirAbacavir may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
AbametapirThe serum concentration of Enzalutamide can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Enzalutamide can be increased when combined with Abatacept.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Enzalutamide.
AcalabrutinibThe metabolism of Enzalutamide can be increased when combined with Acalabrutinib.
AcarboseAcarbose may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Enzalutamide.
AcetaminophenAcetaminophen may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of enzalutamide and may reduce its serum concentration.
  • Take with or without food.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XtandiCapsule40 mgOralAstellas Pharma Europe Bv2013-06-21Not applicableEu
XtandiCapsule40 mgOralAstellas Pharma Inc2013-06-07Not applicableCanada
XtandiCapsule40 mg/1OralAstellas Pharma US, Inc.2012-08-31Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L02BB04 — Enzalutamide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylimidazolidines. These are polycyclic compounds containing an imidazoline substituted by a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolidines
Sub Class
Imidazolidines
Direct Parent
Phenylimidazolidines
Alternative Parents
Trifluoromethylbenzenes / 2-halobenzoic acids and derivatives / Alpha amino acids and derivatives / N-phenylthioureas / Benzamides / Benzoyl derivatives / Benzonitriles / Fluorobenzenes / Aryl fluorides / Imidazolidinones
show 11 more
Substituents
2-halobenzoic acid or derivatives / Alkyl fluoride / Alkyl halide / Alpha-amino acid or derivatives / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzamide / Benzenoid
show 29 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
benzamides, nitrile, imidazolidinone, monofluorobenzenes, (trifluoromethyl)benzenes, thiocarbonyl compound (CHEBI:68534)

Chemical Identifiers

UNII
93T0T9GKNU
CAS number
915087-33-1
InChI Key
WXCXUHSOUPDCQV-UHFFFAOYSA-N
InChI
InChI=1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
IUPAC Name
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide
SMILES
CNC(=O)C1=C(F)C=C(C=C1)N1C(=S)N(C(=O)C1(C)C)C1=CC=C(C#N)C(=C1)C(F)(F)F

References

General References
  1. Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, Gao AC: NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013 Aug;12(8):1629-37. doi: 10.1158/1535-7163.MCT-13-0027. Epub 2013 May 22. [PubMed:23699654]
KEGG Drug
D10218
PubChem Compound
15951529
PubChem Substance
175427141
ChemSpider
13093347
BindingDB
50425732
RxNav
1307298
ChEBI
68534
ChEMBL
CHEMBL1082407
ZINC
ZINC000034806477
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Enzalutamide
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (393 KB)
MSDS
Download (89.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer1
4Active Not RecruitingTreatmentMetastatic Hormone Refractory Prostate Cancer1
4Active Not RecruitingTreatmentProstate Cancer2
4CompletedTreatmentMetastatic Castration Resistant Prostate Cancer1
4CompletedTreatmentMetastatic Castration-Resistant Prostate Cancer (mCRPC)1
4RecruitingSupportive CareCastration-Resistant Prostatic Cancer / Hormone-Refractory Prostate Cancer / Metastatic Hormone Refractory Prostate Cancer / Recurrent Prostate Carcinoma / Stage IV Prostate Cancer1
4RecruitingTreatmentProstatic Neoplasms, Castration-Resistant1
4TerminatedTreatmentMetastatic Castration Resistant Prostate Cancer1
3Active Not RecruitingTreatmentAdenocarcinoma of the Prostate / Hormone-Resistant Prostate Cancer / Recurrent Prostate Cancer / Stage IV Prostate Cancer1
3Active Not RecruitingTreatmentHormone Sensitive Prostate Cancer / Prostate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral40 mg
CapsuleOral40 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8183274No2012-05-222026-05-15Us
US9126941No2015-09-082026-05-15Us
US7709517No2010-05-042027-08-13Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00136 mg/mLALOGPS
logP3.75ALOGPS
logP4.16ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)13.05ChemAxon
pKa (Strongest Basic)-1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area76.44 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity113.48 m3·mol-1ChemAxon
Polarizability42.71 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9356
Blood Brain Barrier+0.8514
Caco-2 permeable+0.5219
P-glycoprotein substrateNon-substrate0.7609
P-glycoprotein inhibitor IInhibitor0.6464
P-glycoprotein inhibitor IIInhibitor0.5693
Renal organic cation transporterNon-inhibitor0.899
CYP450 2C9 substrateNon-substrate0.7447
CYP450 2D6 substrateNon-substrate0.8061
CYP450 3A4 substrateSubstrate0.5589
CYP450 1A2 substrateNon-inhibitor0.5613
CYP450 2C9 inhibitorInhibitor0.7126
CYP450 2D6 inhibitorNon-inhibitor0.9148
CYP450 2C19 inhibitorInhibitor0.6882
CYP450 3A4 inhibitorInhibitor0.6184
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6711
Ames testNon AMES toxic0.683
CarcinogenicityNon-carcinogens0.7232
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4319 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9911
hERG inhibition (predictor II)Inhibitor0.7079
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 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/MSsplash10-014i-0321900000-b1c610c4a717fdea030e

Targets

Details
1. Androgen receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...
Gene Name
AR
Uniprot ID
P10275
Uniprot Name
Androgen receptor
Molecular Weight
98987.9 Da

Enzymes

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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
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. Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T: Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1. [PubMed:25929560]
  2. FDA table of interactions [Link]
  3. Enzalutamide FDA label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. Golshayan AR, Antonarakis ES: Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer. Core Evid. 2013;8:27-35. doi: 10.2147/CE.S34747. Epub 2013 Apr 4. [PubMed:23589709]
  2. Enzalutamide FDA label [File]
  3. Xtandi Monograph [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
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. Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T: Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1. [PubMed:25929560]
  2. Ezalutamide FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
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
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Enzalutamide FDA Review [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA table of interactions [Link]
  2. Xtandi monograph [File]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da
References
  1. CYTOMEL (liothyronine) FDA label [File]

Transporters

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

Drug created on June 04, 2013 23:12 / Updated on August 05, 2020 23:35

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