Olaparib

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H23FN4O3
Molecular Weight	434.4628
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

FC1=CC=C(CC2=NNC(=O)C3=CC=CC=C23)C=C1C(=O)N4CCN(CC4)C(=O)C5CC5

InChI

InChIKey=FDLYAMZZIXQODN-UHFFFAOYSA-N

InChI=1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)

HIDE SMILES / InChI

Description

Olaparib is an oral inhibitor of poly (ADP-ribose) polymerase enzymes, including PARP1, PARP2, and PARP3 which are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has shown activity in ovarian and breast tumors with known BRCA mutations and was the first FDA approved drug in this class. Lynparza (olaparib) is indicated for treatment of gBRCA-mutated advanced ovarian cancer. Its use together with other chemotherapy medicines can lead to increased effects on the blood resulting in reduction in the numbers of white blood cells and platelets, and anaemia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Poly [ADP-ribose] polymerase 1 7	Inhibitor 8,297	1.94 nM [IC50]
Poly [ADP-ribose] polymerase 2 16	Inhibitor 8,297
Poly [ADP-ribose] polymerase 3 4	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ovarian cancer 157	Primary		Approved 8,429	LYNPARZA

C_max

Value	Dose	Analyte	Population
2.97 μg/mL	100 mg 2 times / day multiple, oral	OLAPARIB blood	Homo sapiens
6.88 μg/mL	300 mg single, oral	OLAPARIB blood	Homo sapiens
3.75 μg/mL	100 mg 2 times / day steady-state, oral	OLAPARIB blood	Homo sapiens
8.27 μg/mL	300 mg 2 times / day steady-state, oral	OLAPARIB blood	Homo sapiens
6.875 ug/mL	300 mg single, oral	OLAPARIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
10.9 μg × h/mL	100 mg 2 times / day multiple, oral	OLAPARIB blood	Homo sapiens
31.7 μg × h/mL	300 mg single, oral	OLAPARIB blood	Homo sapiens
16.7 μg × h/mL	100 mg 2 times / day steady-state, oral	OLAPARIB blood	Homo sapiens
44 μg × h/mL	300 mg 2 times / day steady-state, oral	OLAPARIB blood	Homo sapiens
31.68 ug*h/mL	300 mg single, oral	OLAPARIB plasma	Homo sapiens
43.91 ug*h/mL	300 mg 2 times / day single, oral	OLAPARIB plasma	Homo sapiens
43.9499999999999 ug*h/mL	300 mg 2 times / day single, oral	OLAPARIB plasma	Homo sapiens
36.37 ug*h/mL	300 mg single, oral	OLAPARIB plasma	Homo sapiens
36.53 ug*h/mL	300 mg single, oral	OLAPARIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.17 h	100 mg 2 times / day multiple, oral		OLAPARIB blood	Homo sapiens
6.52 h	300 mg single, oral		OLAPARIB blood	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
18%			OLAPARIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
600 mg 2 times / day steady, oral Highest studied dose	unhealthy n = 52
300 mg 2 times / day steady, oral Recommended	unhealthy n = 195	Disc. AE: Anemia, Anemia...
300 mg 2 times / day steady, oral Recommended	unhealthy n = 195	Disc. AE: Fatigue, Fatigue... Other AEs: Diarrhea, Diarrhea...
300 mg 2 times / day steady, oral Recommended	unhealthy n = 195	Disc. AE: Thrombocytopenia, Myelodysplastic syndrome...
400 mg 2 times / day steady, oral Recommended\|MTD	unhealthy n = 223	Disc. AE: Nausea, Nausea...

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AEs

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AE	Significance	Dose	Population
Neutropenia	9% Disc. AE	300 mg 2 times / day steady, oral Recommended	unhealthy n = 195
Anemia	grade 1-2, 24% Disc. AE	300 mg 2 times / day steady, oral Recommended	unhealthy n = 195
Vomiting	grade 1-2, 34% Disc. AE	300 mg 2 times / day steady, oral Recommended	unhealthy n = 195
Nausea	grade 1-2, 73% Disc. AE	300 mg 2 times / day steady, oral Recommended	unhealthy n = 195
Anemia	grade 3-4, 20% Disc. AE	300 mg 2 times / day steady, oral Recommended	unhealthy n = 195

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inducer 389 inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT 4 OCT1 512 OCT2 647 OAT3 642 MATE1 306 MATE2 263 OATP1B1 788 MRP2 383 CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A 214 BCRP 699 P-gp 1,461	CYP3A 191 CYP2A6 543 CYP1A1 349 P-gp 1,537 BCRP 561	CYP2B6 547 CYP1A2 701 CYP2C19 293 CYP3A 129

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no [Inhibition >100 uM]
CYP2A6 739	inhibitor 3,277	no [Inhibition >100 uM]
CYP2B6 1,001	inhibitor 3,277	no [Inhibition >100 uM]
CYP2C19 1,553	inhibitor 3,277	no [Inhibition >100 uM]
CYP2C8 965	inhibitor 3,277	no [Inhibition >100 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
BCRP 561	substrate 3,367	no
CYP1A1 349	substrate 3,367	yes
CYP2A6 543	substrate 3,367	yes
P-gp 1,537	substrate 3,367	yes
CYP3A 191	substrate 3,367	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:83766	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:83766
ChemicalBook	CB02473811	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02473811
ChemicalBook	CB02756176	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02756176
MolPort	MolPort-009-679-395	https://www.molport.com/shop/molecule-link/MolPort-009-679-395
Selleck Chemicals	AZD2281(Olaparib)	http://www.selleckchem.com/products/AZD2281(Olaparib).html

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PubMed

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Title	Date	PubMed
		252160170
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.	2008 Nov 4	18971340
4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.	2008 Oct 23	18800822
Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes.	2009	19589159
Triple-negative breast cancer: novel therapies and new directions.	2009 Aug 20	19632796

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Patents

Sample Use Guides

In Vivo Use Guide

400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.

Route of Administration: Oral

In Vitro Use Guide

30-100 nM in SW620 cells

Show entries

Name

Type

Language

Olaparib

Official Name

English

Olaparib [WHO-DD]

Common Name

English

AZD2281

Code

English

KEYLYNK-010 COMPONENT OLAPARIB

Code

English

OLAPARIB [USAN]

Common Name

English

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Classification Tree

Code System

Code

Established Pharmacologic Class

NDF-RT

N0000191623

GENITAL NEOPLASMS, FEMALE

EMA ASSESSMENT REPORTS

LYNPARZA (AUTHORIZED: OVARIAN NEOPLASMS)

Designated/Approved

FDA ORPHAN DRUG

419013

Designated/Approved

FDA ORPHAN DRUG

417613

Withdrawn

EU-Orphan Drug

EU/3/07/501

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Code System

Code

Type

Description

DAILYMED

WOH1JD9AR8

PRIMARY

EVMPD

SUB32234

PRIMARY

SMS_ID

100000124466

PRIMARY

MERCK INDEX

m8185

PRIMARY

Merck Index

ChEMBL

CHEMBL521686

PRIMARY

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ACTIVE MOIETY


					WOH1JD9AR8

Olaparib

SALT/SOLVATE (PARENT)


					34FMX7983W

Olaparib monohydrate

SALT/SOLVATE (PARENT)


					Q67E7B7KG6

Olaparib hemi-2-propanol

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator