ABIRATERONE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H31NO
Molecular Weight	349.509
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CC=C(C3=CC=CN=C3)[C@@]1(C)CC[C@@]4([H])[C@@]2([H])CC=C5C[C@@H](O)CC[C@]45C

InChI

InChIKey=GZOSMCIZMLWJML-VJLLXTKPSA-N

InChI=1S/C24H31NO/c1-23-11-9-18(26)14-17(23)5-6-19-21-8-7-20(16-4-3-13-25-15-16)24(21,2)12-10-22(19)23/h3-5,7,13,15,18-19,21-22,26H,6,8-12,14H2,1-2H3/t18-,19-,21-,22-,23-,24+/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202379s023lbl.pdf
Curator's Comment: description was created based on several sources, including http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002321/WC500112860.pdf

Abiraterone acetate (trade name Zytiga) is a prodrug to the abiraterone, steroidal compound with antiandrogen activity and a 17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor. It is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. Abiraterone acetate is converted in vivo to abiraterone which inhibits CYP17, enzyme expressed in testicular, adrenal, and prostatic tumor tissues and required for androgen biosynthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenals to castrate-range levels. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytochrome P450 17A1 8 Target ID: CHEMBL3522 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20645691	Inhibitor 8297		110.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Metastatic castration-resistant prostate cancer 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202379s023lbl.pdf	Primary		Approved 8429	ZYTIGA Approved Use Indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. Launch Date 2011

C_max

Value	Dose	Analyte	Population
226 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202379s005lbl.pdf	1000 mg 1 times / day steady-state, oral dose: 1000 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
297 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
12.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
50.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
60.6 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
85.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
71.9 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
64.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
1173 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202379s005lbl.pdf	1000 mg 1 times / day steady-state, oral dose: 1000 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1562 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
177 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
315 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
315 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
330 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
365 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
461 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
18.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
18.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
18.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
18.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
13.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
17.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
15.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374856/	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:	ABIRATERONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Co-administed with:: Corticosteroid Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf	unhealthy, 70 years n = 542 Health Status: unhealthy Condition: metastatic castrationresistant prostate cancer Age Group: 70 years Sex: M Population Size: 542 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf	Disc. AE: Cardiac failure, AST high... Other AEs: Lymphopenia, Lymphopenia... AEs leading to discontinuation/dose reduction: Cardiac failure (5 patients) AST high (1%) ALT high (1%) Other AEs: Lymphopenia (grade 1-2, 29.3%) Lymphopenia (grade 3-4, 8.7%) Hyperglycemia (grade 1-2, 50.5%) Hyperglycemia (grade 3-4, 6.5%) ALT high (grade 1-2, 35.9%) ALT high (grade 3-4, 6.1%) AST high (grade 1-2, 33.9%) AST high (grade 3-4, 3.1%) Hypernatremia (grade 1-2, 32.6%) Hypernatremia (grade 3-4, 0.4%) Hypokalemia (grade 1-2, 14.2%) Hypokalemia (grade 3-4, 2.8%) Cardiac failure (grade 3-4, 1.6%) Cardiac failure (grade 5, 2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf
500 mg 1 times / day steady, oral Recommended Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Co-administed with:: Corticosteroid Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf	unhealthy, 70 years n = 546 Health Status: unhealthy Condition: metastatic castrationresistant prostate cancer Age Group: 70 years Sex: M Population Size: 546 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf	Other AEs: Fatigue, Fatigue... Other AEs: Fatigue (grade 1-2, 39%) Fatigue (grade 3-4, 2.2%) Edema peripheral (grade 1-2, 25%) Pitting edema (grade 1-2, 25%) Generalized edema (grade 1-2, 25%) Pyrexia (grade 1-2, 8.7%) Pyrexia (grade 3-4, 0.6%) Arthritis (grade 1-2, 30%) Arthralgia (grade 1-2, 30%) Joint swelling (grade 1-2, 30%) Joint stiffness (grade 1-2, 30%) Groin pain (grade 1-2, 6.6%) Constipation (grade 1-2, 23%) Diarrhea (grade 1-2, 22%) Dyspepsia (grade 1-2, 11%) Hot flush (grade 1-2, 22%) Hot flush (grade 3-4, 0.2%) Hypertension (grade 1-2, 22%) Hypertension (grade 3-4, 3.9%) Cough (grade 1-2, 17%) Dyspnea (grade 1-2, 12%) Dyspnea (grade 3-4, 2.4%) Insomnia (grade 1-2, 14%) Insomnia (grade 3-4, 0.2%) Contusion (grade 1-2, 13%) Fall (grade 1-2, 5.9%) Upper respiratory tract infection (grade 1-2, 13%) Nasopharyngitis (grade 1-2, 8%) Hematuria (grade 1-2, 10%) Hematuria (grade 3-4, 1.3%) Rash (grade 1-2, 8.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf
2000 mg 1 times / day multiple, oral Highest studied dose Dose: 2000 mg, 1 times / day Route: oral Route: multiple Dose: 2000 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf Page: p. 27	unhealthy Health Status: unhealthy Condition: metastatic castrationresistant prostate cancer Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf Page: p. 27	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf Page: p. 27

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2E1 882 CYP2C19 1478 CYP3A4/5 278 CYP2A6 707 P-gp 1461	SULT2A1 24 P-gp 1537 UGT1A4 347 UGT1A3 422

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no	ABIRATERONE 2
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no	ABIRATERONE 2
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=25 Page: 25.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	strong [Ki 0.16 uM]		yes (co-administration study) Comment: The systemic exposure of dextromethorphan (CYP2D6 substrate) as assessed by the ratios of the geometric mean for Cmax and AUC, were approximately 2.8- and 2.9-fold higher, respectively, when dextromethorphan was co-administered with abiraterone acetate Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=8 Page: 8.0
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	strong [Ki 0.32 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 42.0	yes [IC50 10.8 uM]	ABIRATERONE 2
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 0.12 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 0.39 uM]	ABIRATERONE 2
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 0.44 uM]	ABIRATERONE 2
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 11.4 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 17.6 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 29.8 uM]	ABIRATERONE 2
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 31.8 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 46.3 uM]	ABIRATERONE 2
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [Ki 8.01 uM]	ABIRATERONE 2

Drug as victim

Target	Modality	Activity	Metabolite
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=26 Page: 26.0	major
UGT1A3 422	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=26 Page: 26.0	minor
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=23 Page: 23.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=23 Page: 23.0	no	ABIRATERONE 2
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes
SULT2A1 24	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes

PubMed

Title	Date	PubMed
Efficacy of abiraterone acetate in post-docetaxel castration-resistant prostate cancer.	2010 Jul	20645691
Abiraterone acetate.	2011 Aug 1	21804589
[Abiraterone acetate: a novel therapeutic option in hormone-refractory prostate cancer].	2012 Feb	22430753
Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men.	2012 Jun	22526411
Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay.	2014 Mar	24284787

Patents

Sample Use Guides

In Vivo Use Guide

1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Zytiga must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Zytiga is taken and for at least one hour after the dose of Zytiga is taken. For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the Zytiga starting dose to 250 mg once daily. For patients who develop hepatotoxicity during treatment, hold Zytiga until recovery. Retreatment may be initiated at a reduced dose. Zytiga should be discontinued if patients develop severe hepatotoxicity.

Route of Administration: Oral

In Vitro Use Guide

Abiraterone acetate (CB 7630) inhibits CYP17 with an IC50 of 110 nM in human testicular microsomes. In Caco-2 cell monolayers abiraterone acetate had a low apparent permeability and was not substrate of P-glycoprotein (P-gp). Abiraterone acetate inhibited P-gp significantly at high concentrations with a 50 % inhibitory concentration (IC50) of 10.8 uM however as abiraterone acetate is rapidly converted to abiraterone, no systemic inhibition of P-gp is expected.

Name

Type

Language

ABIRATERONE

Official Name

English

NSC-741232

Code

English

17-(3-PYRIDYL)ANDROSTA-5,16-DIEN-3.BETA.-OL

Systematic Name

English

17-(PYRIDIN-3-YL)ANDROSTA-5,16-DIEN-3.BETA.-OL

Systematic Name

English

Abiraterone [WHO-DD]

Common Name

English

CB 7598

Code

English

ABIRATERONE [VANDF]

Common Name

English

ABIRATERONE [USP IMPURITY]

Common Name

English

ABIRATERONE [MI]

Common Name

English

CB-7598

Code

English

ANDROSTA-5,16-DIEN-3-OL, 17-(3-PYRIDINYL)-(3.BETA.)-

Systematic Name

English

abiraterone [INN]

Common Name

English

Classification Tree Code System Code

LIVERTOX

NBK548136