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Details

Stereochemistry ACHIRAL
Molecular Formula C21H15F4N5O2S
Molecular Weight 477.4366
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of APALUTAMIDE

SMILES

CN=C(c1ccc(cc1F)N2C(=S)N(c3cc(c(C#N)nc3)C(F)(F)F)C(=O)C42CCC4)O

InChI

InChIKey=HJBWBFZLDZWPHF-UHFFFAOYSA-N
InChI=1S/C21H15F4N5O2S/c1-27-17(31)13-4-3-11(8-15(13)22)30-19(33)29(18(32)20(30)5-2-6-20)12-7-14(21(23,24)25)16(9-26)28-10-12/h3-4,7-8,10H,2,5-6H2,1H3,(H,27,31)

HIDE SMILES / InChI

Molecular Formula C21H15F4N5O2S
Molecular Weight 477.4366
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment:: https://www.ncbi.nlm.nih.gov/pubmed/22266222

Apalutamide (developmental code name ARN-509) is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM, useful for prostate cancer treatment. Apalutamide binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells. Apalutamide is currently in phase III clinical trials for castration-resistant prostate cancer.

CNS Activity

Curator's Comment:: weak CNS effect "Apalutamide binds weakly to the GABAA receptor"

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
16 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ERLEADA

Approved Use

ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.

Launch Date

1518480000000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
6 μg/mL
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
APALUTAMIDE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
100 μg × h/mL
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
APALUTAMIDE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
72 h
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
APALUTAMIDE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
4%
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
APALUTAMIDE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
480 mg 1 times / day multiple, oral
Highest studied dose
Dose: 480 mg, 1 times / day
Route: oral
Route: multiple
Dose: 480 mg, 1 times / day
Sources:
unhealthy, 68 years (range: 45 - 81 yers)
Health Status: unhealthy
Age Group: 68 years (range: 45 - 81 yers)
Sex: M
Sources:
300 mg 1 times / day multiple, oral
Dose: 300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 300 mg, 1 times / day
Sources:
unhealthy, 68 years (range: 45 - 81 yers)
Health Status: unhealthy
Age Group: 68 years (range: 45 - 81 yers)
Sex: M
Sources:
DLT: Abdominal pain...
Dose limiting toxicities:
Abdominal pain (grade 3, 1 patient)
Sources:
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Disc. AE: Rash, Rash...
AEs leading to
discontinuation/dose reduction:
Rash (3%)
Rash (>1)
Diarrhea (>1)
Fatigue (>1)
Nausea (>1)
Vomiting (>1)
Hypertension (>1)
Hematuria (>1)
Sources:
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Disc. AE: Fatigue, Decreased appetite...
AEs leading to
discontinuation/dose reduction:
Fatigue (1%)
Decreased appetite (0.7%)
Weight decreased (0.7%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Abdominal pain grade 3, 1 patient
DLT, Disc. AE
300 mg 1 times / day multiple, oral
Dose: 300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 300 mg, 1 times / day
Sources:
unhealthy, 68 years (range: 45 - 81 yers)
Health Status: unhealthy
Age Group: 68 years (range: 45 - 81 yers)
Sex: M
Sources:
Rash 3%
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Diarrhea >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Fatigue >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Hematuria >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Hypertension >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Nausea >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Rash >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Vomiting >1
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Decreased appetite 0.7%
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Weight decreased 0.7%
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
Fatigue 1%
Disc. AE
240 mg 1 times / day steady, oral
Recommended|MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: steady
Dose: 240 mg, 1 times / day
Sources:
unhealthy, 74 years (range: 48-97 years)
Health Status: unhealthy
Age Group: 74 years (range: 48-97 years)
Sex: M
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
yes [IC50 12 uM]
yes [IC50 13.8 uM]
yes [IC50 27.2 uM]
yes [IC50 37.9 uM]
yes [IC50 4.8 uM]
yes [IC50 7.6 uM]
yes [Ki 0.3 uM]
yes [Ki 27 uM]
yes [Ki 28 uM]
yes [Ki 33.5 uM]
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes (co-administration study)
Comment: co-administration of apalutamide 240 QD with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate).
Page: 66
yes
yes (co-administration study)
Comment: co-administration of apalutamide 240 QD with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate).
Page: 66
yes
yes (co-administration study)
Comment: co-administration of apalutamide 240 QD with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate).
Page: 66
Drug as victim

Drug as victim

Tox targets
PubMed

PubMed

TitleDatePubMed
ARN-509: a novel antiandrogen for prostate cancer treatment.
2012 Mar 15
New agents for prostate cancer.
2014 Sep
Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.
2016 Dec
Patents

Sample Use Guides

The recommended dose of ERLEADA (apalutamide) is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food.
Route of Administration: Oral
APALUTAMIDE binds AR with IC50 16 nM
Substance Class Chemical
Created
by admin
on Sat Jun 26 11:56:53 UTC 2021
Edited
by admin
on Sat Jun 26 11:56:53 UTC 2021
Record UNII
4T36H88UA7
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
APALUTAMIDE
INN   WHO-DD  
INN  
Official Name English
APALUTAMIDE [ORANGE BOOK]
Common Name English
4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)PYRIDIN-3-YL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO(3.4)OCTAN-5-YL)-2-FLUORO-N-METHYLBENZAMIDE
Systematic Name English
ERLEADA
Brand Name English
APALUTAMIDE [MI]
Common Name English
APALUTAMIDE [INN]
Common Name English
BENZAMIDE, 4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)-3-PYRIDINYL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO(3.4)OCT-5-YL)-2-FLUORO-N-METHYL-
Systematic Name English
JNJ-56021927
Code English
APALUTAMIDE [JAN]
Common Name English
ARN-509
Code English
APALUTAMIDE [WHO-DD]
Common Name English
Classification Tree Code System Code
WHO-ATC L02BB05
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
NCI_THESAURUS C146993
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
Code System Code Type Description
DRUG BANK
DB11901
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
PUBCHEM
24872560
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
INN
10118
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
FDA UNII
4T36H88UA7
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
CAS
956104-40-8
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
EPA CompTox
956104-40-8
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
RXCUI
1999574
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
ChEMBL
CHEMBL3183409
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
MERCK INDEX
M12063
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
DRUG CENTRAL
5278
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
NCI_THESAURUS
C92574
Created by admin on Sat Jun 26 11:56:54 UTC 2021 , Edited by admin on Sat Jun 26 11:56:54 UTC 2021
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
IC50
METABOLIC ENZYME -> SUBSTRATE
CUMULATIVE EXCRETION
URINE
BINDER->LIGAND
BINDING
CUMULATIVE EXCRETION
FECAL
TRANSPORTER -> INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
, coadministration of omeprazole, a CYP2C19 substrate, with multiple daily doses of 240 mg apalutamide decreased the omeprazole AUC by 85%
EXCRETED UNCHANGED
FECAL
TARGET -> INHIBITOR
The binding affinities of apalutamide to the ligand binding domains of AR and PR, and to full-length ER? and GR demonstrate that it is relatively selective for AR (
IC50
TRANSPORTER -> INHIBITOR
IC50
OFF-TARGET->INHIBITOR
OFF-TARGET ACTIVITY: INHIBITING LIGAND BINDING TO THE GABAA CHLORIDE ION CHANNEL
BINDING
IC50
EXCRETED UNCHANGED
URINE
METABOLIC ENZYME -> INDUCER
coadministration of S-warfarin, a CYP2C9 substrate, with multiple daily doses of 240 mg apalutamide decreased the S-warfarin AUC by 46%
METABOLIC ENZYME -> SUBSTRATE
Due to CYP3A4 auto-induction, the contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
OFF-TARGET->INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
coadministration of midazolam, a CYP3A4 substrate, with multiple daily doses of 240 mg apalutamide decreased the midazolam AUC by 92%
Related Record Type Details
METABOLITE -> PARENT
PLASMA
METABOLITE ACTIVE -> PARENT
Due to CYP3A4 auto-induction, the contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
MAJOR
METABOLITE INACTIVE -> PARENT
after oral administration of 240 mg of apalutamide in 0-1680 hours
URINE
METABOLITE -> PARENT
after oral administration of 240 mg of apalutamide in 0-1680 hours
FECAL
METABOLITE ACTIVE -> PARENT
Due to CYP3A4 auto-induction, the contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
MAJOR
METABOLITE -> PARENT
after oral administration of 240 mg of apalutamide in 0-1680 hours
FECAL
METABOLITE -> PARENT
URINE
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC ROUTE OF ADMINISTRATION
PHARMACOKINETIC
DOSE
PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC ROUTE OF ADMINISTRATION
PHARMACOKINETIC
DOSE
PHARMACOKINETIC
Cmax PHARMACOKINETIC ROUTE OF ADMINISTRATION
PHARMACOKINETIC
DOSE
PHARMACOKINETIC
Tmax PHARMACOKINETIC ROUTE OF ADMINISTRATION
PHARMACOKINETIC
DOSE
PHARMACOKINETIC
Tmax PHARMACOKINETIC DOSE
PHARMACOKINETIC
ROUTE OF ADMINISTRATION
PHARMACOKINETIC