Enzalutamide

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Enzalutamide (DB08899)

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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

• Metastatic Castration Resistant Prostate Cancer

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.

Target	Actions	Organism
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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
Abametapir	The serum concentration of Enzalutamide can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Enzalutamide can be increased when combined with Abatacept.
Abiraterone	The metabolism of Abiraterone can be increased when combined with Enzalutamide.
Acalabrutinib	The metabolism of Enzalutamide can be increased when combined with Acalabrutinib.
Acarbose	Acarbose may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Enzalutamide which could result in a higher serum level.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Enzalutamide.
Acetaminophen	Acetaminophen 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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Xtandi	Capsule	40 mg	Oral	Astellas Pharma Europe Bv	2013-06-21	Not applicable
Xtandi	Tablet	40 mg/1	Oral	Astellas Pharma US, Inc.	2020-08-04	Not applicable
Xtandi	Capsule		Oral	Astellas Pharma Inc	2013-06-07	Not applicable
Xtandi	Capsule	40 mg/1	Oral	Astellas Pharma US, Inc.	2012-08-31	Not applicable
Xtandi	Tablet	80 mg/1	Oral	Astellas Pharma US, Inc.	2020-08-04	Not applicable

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

• L02BB — Anti-androgens
• L02B — HORMONE ANTAGONISTS AND RELATED AGENTS
• L02 — ENDOCRINE THERAPY
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Androgen Receptor Antagonists
• Androgen Receptor Inhibitor
• Antiandrogens
• Antiandrogens, non-steroidal
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (moderate)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (moderate)
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (moderate)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inducers (strong)
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strong)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inducers
• Cytochrome P-450 CYP3A5 Inducers (strong)
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Endocrine Therapy
• Hormone Antagonists and Related Agents
• Hydantoins
• Imidazoles
• Imidazolidines
• P-glycoprotein inhibitors
• Thyroxine-binding globulin substrates

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 / Vinylogous halides / Thioureas / Secondary carboxylic acid amides / Nitriles / Azacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organofluorides / Alkyl fluorides / Organopnictogen compounds

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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 / Benzoic acid or derivatives / Benzonitrile / Benzoyl / Carbonitrile / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Fluorobenzene / Halobenzene / Halobenzoic acid or derivatives / Hydrocarbon derivative / Imidazolidinone / Monocyclic benzene moiety / N-phenylthiourea / Nitrile / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Organosulfur compound / Phenylimidazolidine / Secondary carboxylic acid amide / Thiourea / Trifluoromethylbenzene / Vinylogous halide

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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]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Metastatic Castration Resistant Prostate Cancer	1
4	Active Not Recruiting	Treatment	Metastatic Hormone Refractory Prostate Cancer	1
4	Active Not Recruiting	Treatment	Prostate Cancer	1
4	Completed	Treatment	Metastatic Castration Resistant Prostate Cancer	1
4	Completed	Treatment	Metastatic Castration-Resistant Prostate Cancer (mCRPC)	1
4	Completed	Treatment	Prostate Cancer	1
4	Recruiting	Supportive Care	Castration-Resistant Prostatic Cancer / Hormone-Refractory Prostate Cancer / Metastatic Hormone Refractory Prostate Cancer / Recurrent Prostate Carcinoma / Stage IV Prostate Cancer	1
4	Recruiting	Treatment	Prostatic Neoplasms, Castration-Resistant	1
4	Terminated	Treatment	Metastatic Castration Resistant Prostate Cancer	1
3	Active Not Recruiting	Treatment	Adenocarcinoma of the Prostate / Hormone-Resistant Prostate Cancer / Recurrent Prostate Cancer / Stage IV Prostate Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule
Capsule	Oral	40 mg/1
Capsule	Oral	40 mg
Tablet	Oral	40 mg/1
Tablet	Oral	80 mg/1
Tablet, film coated	Oral	40 MG
Tablet, film coated	Oral	80 MG
Capsule, liquid filled	Oral	40 mg
Capsule		40 mg
Capsule	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US8183274	No	2012-05-22	2026-05-15
US9126941	No	2015-09-08	2026-05-15
US7709517	No	2010-05-04	2027-08-13

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

Property	Value	Source
water solubility	Insoluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.00136 mg/mL	ALOGPS
logP	3.75	ALOGPS
logP	4.16	ChemAxon
logS	-5.5	ALOGPS
pKa (Strongest Acidic)	13.05	ChemAxon
pKa (Strongest Basic)	-1.7	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	76.44 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	113.48 m3·mol-1	ChemAxon
Polarizability	42.71 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9356
Blood Brain Barrier	+	0.8514
Caco-2 permeable	+	0.5219
P-glycoprotein substrate	Non-substrate	0.7609
P-glycoprotein inhibitor I	Inhibitor	0.6464
P-glycoprotein inhibitor II	Inhibitor	0.5693
Renal organic cation transporter	Non-inhibitor	0.899
CYP450 2C9 substrate	Non-substrate	0.7447
CYP450 2D6 substrate	Non-substrate	0.8061
CYP450 3A4 substrate	Substrate	0.5589
CYP450 1A2 substrate	Non-inhibitor	0.5613
CYP450 2C9 inhibitor	Inhibitor	0.7126
CYP450 2D6 inhibitor	Non-inhibitor	0.9148
CYP450 2C19 inhibitor	Inhibitor	0.6882
CYP450 3A4 inhibitor	Inhibitor	0.6184
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.6711
Ames test	Non AMES toxic	0.683
Carcinogenicity	Non-carcinogens	0.7232
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.4319 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9911
hERG inhibition (predictor II)	Inhibitor	0.7079

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-014i-0321900000-b1c610c4a717fdea030e

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Drug created on June 04, 2013 23:12 / Updated on October 27, 2020 11:13