Olaparib monohydrate

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H23FN4O3.H2O
Molecular Weight	452.4781
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=IZBKJWSFXCKAPD-UHFFFAOYSA-N

InChI=1S/C24H23FN4O3.H2O/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);1H2

HIDE SMILES / InChI

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C24H23FN4O3
Molecular Weight	434.4628
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf
Curator's Comment: Description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880823/

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 Target ID: P09874 Gene ID: 142.0 Gene Symbol: PARP1 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/27487106	Inhibitor 8297	1.94 nM [IC50]
Poly [ADP-ribose] polymerase 2 16 Target ID: Q9UGN5 Gene ID: 10038.0 Gene Symbol: PARP2 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/27487106	Inhibitor 8297
Poly [ADP-ribose] polymerase 3 4 Target ID: Q9Y6F1 Gene ID: 10039.0 Gene Symbol: PARP3 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/27487106	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ovarian cancer 157 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	Primary		Approved 8429	LYNPARZA Approved Use Monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Launch Date 2014

C_max

Value	Dose	Analyte	Population
2.97 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.88 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.75 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.27 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.875 ug/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:

AUC

Value	Dose	Analyte	Population
10.9 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.7 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16.7 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
44 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.68 ug*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:
43.91 ug*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg 2 times / day single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:
43.9499999999999 ug*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg 2 times / day single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:
36.37 ug*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:
36.53 ug*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02430311	300 mg single, oral dose: 300 mg route of administration: oral experiment type: single co-administered:	OLAPARIB plasma	Homo sapiens population: unhealthy age: sex: food status:

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.17 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.52 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30887180	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		OLAPARIB blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
18% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf			OLAPARIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf Page: p. 8	unhealthy n = 52 Health Status: unhealthy Condition: advanced solid tumors Population Size: 52 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf Page: p. 8	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf Page: p. 8
300 mg 2 times / day steady, oral Recommended Dose: 300 mg, 2 times / day Route: oral Route: steady Dose: 300 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf	unhealthy n = 195 Health Status: unhealthy Condition: gBRCAm ovarian cancer Population Size: 195 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf	Disc. AE: Anemia, Anemia... AEs leading to discontinuation/dose reduction: Anemia (grade 1-2, 24%) Anemia (grade 3-4, 20%) Neutropenia (9%) Nausea (grade 1-2, 73%) Nausea (grade 3-4, 3%) Vomiting (grade 1-2, 34%) Vomiting (grade 3-4, 3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf
300 mg 2 times / day steady, oral Recommended Dose: 300 mg, 2 times / day Route: oral Route: steady Dose: 300 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf	unhealthy n = 195 Health Status: unhealthy Condition: gBRCAm ovarian cancer Population Size: 195 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf	Disc. AE: Fatigue, Fatigue... Other AEs: Diarrhea, Diarrhea... AEs leading to discontinuation/dose reduction: Fatigue (grade 1-2, 62%) Fatigue (grade 3-4, 4%) Other AEs: Diarrhea (grade 1-2, 31%) Diarrhea (grade 3-4, 2%) Abscess oral (grade 1-2, 19%) Aphthous ulcer (grade 1-2, 19%) Gingival abscess (grade 1-2, 19%) Gingival disorder (grade 1-2, 19%) Gingival pain (grade 1-2, 19%) Gingivitis (grade 1-2, 19%) Mouth ulceration (grade 1-2, 19%) Mucosal infection (grade 1-2, 19%) Mucosal inflammation (grade 1-2, 19%) Oral candidiasis (grade 1-2, 19%) Oral discomfort (grade 1-2, 19%) Oral herpes (grade 1-2, 19%) Oral infection (grade 1-2, 19%) Oral mucosal erythema (grade 1-2, 19%) Oral pain (grade 1-2, 19%) Oropharyngeal discomfort (grade 1-2, 19%) Oropharyngeal pain (grade 1-2, 19%) Abscess oral (grade 3-4, 1%) Aphthous ulcer (grade 3-4, 1%) Gingival abscess (grade 3-4, 1%) Gingival disorder (grade 3-4, 1%) Gingival pain (grade 3-4, 1%) Gingivitis (grade 3-4, 1%) Mouth ulceration (grade 3-4, 1%) Mucosal infection (grade 3-4, 1%) Mucosal inflammation (grade 3-4, 1%) Oral candidiasis (grade 3-4, 1%) Oral discomfort (grade 3-4, 1%) Oral herpes (grade 3-4, 1%) Oral infection (grade 3-4, 1%) Oral mucosal erythema (grade 3-4, 1%) Oral pain (grade 3-4, 1%) Oropharyngeal discomfort (grade 3-4, 1%) Oropharyngeal pain (grade 3-4, 1%) Nasopharyngitis (grade 1-4, 36%) Sinusitis (grade 1-4, 36%) Rhinitis (grade 1-4, 36%) Influenza (grade 1-4, 36%) Decreased appetite (grade 1-4, 22%) Arthralgia (grade 1-4, 30%) Myalgia (grade 1-4, 30%) Dysgeusia (grade 1-4, 27%) Headache (grade 1-2, 25%) Headache (grade 3-4, 1%) Rash (<20%) Cough (<20%) Dyspepsia (<20%) Leukopenia (<20%) Hypomagnesemia (<20%) Dizziness (<20%) Thrombocytopenia (<20%) Creatinine increased (<20%) Lymphopenia (<20%) Edema (<20%) Mean corpuscular volume increased (grade 1-4, 89%) Decreased hemoglobin (grade 1-2, 66%) Decreased hemoglobin (grade 3-4, 17%) Leukocyte count decreased (grade 1-2, 64%) Leukocyte count decreased (grade 3-4, 5%) Lymphocyte count low (grade 1-2, 56%) Lymphocyte count low (grade 3-4, 11%) Absolute neutrophil count decreased (grade 1-2, 44%) Absolute neutrophil count decreased (grade 3-4, 7%) Creatinine serum increased (grade 1-4, 44%) Platelets decreased (grade 1-2, 40%) Platelets decreased (grade 3-4, 2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf
300 mg 2 times / day steady, oral Recommended Dose: 300 mg, 2 times / day Route: oral Route: steady Dose: 300 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf Page: p. 99	unhealthy n = 195 Health Status: unhealthy Condition: gBRCAm ovarian cancer Population Size: 195 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf Page: p. 99	Disc. AE: Thrombocytopenia, Myelodysplastic syndrome... AEs leading to discontinuation/dose reduction: Thrombocytopenia (9 patients) Myelodysplastic syndrome (2 patients) Acute myeloid leukemia (2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf Page: p. 99
400 mg 2 times / day steady, oral Recommended\|MTD Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf	unhealthy n = 223 Health Status: unhealthy Condition: gBRCA-mutated advanced ovarian cancer Population Size: 223 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf	Disc. AE: Nausea, Nausea... AEs leading to discontinuation/dose reduction: Nausea (grade 1-2, 61%) Nausea (grade 3-4, 3%) Vomiting (grade 1-2, 39%) Vomiting (grade 3-4, 4%) Fatigue (grade 1-2, 58%) Fatigue (grade 3-4, 8%) Anemia (grade 1-2, 75%) Anemia (grade 3-4, 15%) Thrombocytopenia (grade 1-2, 27%) Thrombocytopenia (grade 3-4, 3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208558Orig1s000MultidisciplineR.pdf
400 mg 2 times / day steady, oral Recommended\|MTD Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	unhealthy Health Status: unhealthy Condition: gBRCA-mutated advanced ovarian cancer Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	Disc. AE: Pneumonitis... AEs leading to discontinuation/dose reduction: Pneumonitis (grade 5, <1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf
400 mg 2 times / day steady, oral Recommended\|MTD Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	unhealthy n = 223 Health Status: unhealthy Condition: gBRCA-mutated advanced ovarian cancer Population Size: 223 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	Other AEs: Anemia, Anemia... Other AEs: Anemia (grade 1-2, 16%) Anemia (grade 3-4, 18%) Abdominal discomfort (grade 1-2, 35%) Abdominal discomfort (grade 3-4, 8%) Decreased appetite (grade 1-2, 21%) Decreased appetite (grade 3-4, 1%) Diarrhea (grade 1-2, 30%) Diarrhea (grade 3-4, 1%) Dyspepsia (grade 1-4, 25%) Asthenia (grade 1-2, 58%) Asthenia (grade 3-4, 8%) Nasopharyngitis (grade 1-4, 26%) Arthralgia (grade 1-4, 21%) Musculoskeletal pain (grade 1-4, 21%) Myalgia (grade 1-4, 22%) Neutropenia (grade 1-2, 18%) Neutropenia (grade 3-4, 7%) Lymphopenia (grade 1-2, 39%) Lymphopenia (grade 3-4, 17%) Mean corpuscular volume increased (grade 1-4, 57%) Creatinine increased (grade 1-2, 28%) Creatinine increased (grade 3-4, 2%) Cough (10-20) Constipation (10-20) Dysgeusia (10-20) Peripheral edema (10-20) Back pain (10-20) Dizziness (10-20) Headache (10-20) Urinary tract infection (10-20) Dyspnea (10-20) Rash (10-20) Leukopenia (1-10) Stomatitis (1-10) Peripheral neuropathy (1-10) Pyrexia (1-10) Hypomagnesemia (1-10) Hyperglycemia (1-10) Anxiety (1-10) Depression (1-10) Insomnia (1-10) Dysuria (1-10) Urinary incontinence (1-10) Vulvovaginal disorder (1-10) Dry skin (1-10) Eczema (1-10) Pruritis (1-10) Hypertension (1-10) Venous thrombosis (1-10) Hot flush (1-10) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf
400 mg 2 times / day steady, oral Recommended\|MTD Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	unhealthy n = 2618 Health Status: unhealthy Condition: gBRCA-mutated advanced ovarian cancer Population Size: 2618 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf	Disc. AE: Myelodysplastic syndrome, Acute myeloid leukemia... AEs leading to discontinuation/dose reduction: Myelodysplastic syndrome (grade 5, <1%) Acute myeloid leukemia (grade 5, <1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inducer 389 inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT 4 OCT1 512 OCT2 647 OAT3 642 MATE1 306 MATE2 263 OATP1B1 788 MRP2 383 CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP3A 214 BCRP 699 P-gp 1461	CYP3A 191 CYP2A6 543 CYP1A1 349 P-gp 1537 BCRP 561	CYP2B6 547 CYP1A2 701 CYP2C19 293 CYP3A 129

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no [Inhibition >100 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=34 Page: -	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 18.4 uM]
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 19.9 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 20.3 uM]
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 37.9 uM]
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 47.1 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes [IC50 5.5 uM]
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	yes [Inhibition 100 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=34 Page: -	yes
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=33 Page: -	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=79 Page: -	yes
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes
OAT 4	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=35 Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=34 Page: -	no
CYP1A1 349	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=29 Page: -	yes
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=29 Page: -	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=34 Page: -	yes
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=4 Page: -	yes	yes (co-administration study) Comment: Itraconazole (strong CYP3A inhibitor) increased the AUC of olaparib by 2.7-fold and PBPK modeling predicted that fluconazole (moderate CYP3A inhibitor) would likely increase olaparib AUC by 2-fold. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf#page=4 Page: -

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000PharmR.pdf#page=58 Page: -

Sourcing

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
ZINC	ZINC000040430143	http://zinc15.docking.org/substances/ZINC000040430143
eMolecules	31526131	https://www.emolecules.com/cgi-bin/more?vid=31526131

PubMed

Title	Date	PubMed
A FlashPlate assay for the identification of PARP-1 inhibitors.	2003 Jun	12857389
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
Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90.	2009 Aug	19671736
Converting cancer mutations into therapeutic opportunities.	2009 Sep	20049732
Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone.	2010	21050423
Present and future evolution of advanced breast cancer therapy.	2010	21050422
Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms.	2010	20459590
Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features.	2010	20149218
Targeted therapies in epithelial ovarian cancer.	2010	20111741
The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer.	2010	20049345
ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors.	2010 Feb	20124459
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.	2010 Jul 24	20609468
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.	2010 Jul 24	20609467
Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair.	2010 Jun	20530711
Targeting poly(ADP-ribose) polymerase activity for cancer therapy.	2010 Nov	20725763
The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.	2010 Nov 25	20739657
Treatment options for patients with triple-negative breast cancer.	2010 Oct 27	20979652
Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil.	2011	22194930
5-Benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2).	2011 Apr 14	21417348
MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor.	2011 Apr 8	21285347
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.	2011 Jul	21633166
Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework.	2014 Jun	24833294
5-Fluorouracil-induced RNA stress engages a TRAIL-DISC-dependent apoptosis axis facilitated by p53.	2015 Dec 22	26544897

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

Substance Class	Chemical Created by `admin` on `Sat Dec 16 20:11:44 GMT 2023` Edited by `admin` on `Sat Dec 16 20:11:44 GMT 2023`
Record UNII	34FMX7983W
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Olaparib monohydrate

Common Name

English

1(2H)-Phthalazinone, 4-[[3-[[4-(cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-, hydrate (1:1)

Common Name

English

Code System Code Type Description

PUBCHEM

168798820

Created by admin on Sat Dec 16 20:11:44 GMT 2023 , Edited by admin on Sat Dec 16 20:11:44 GMT 2023

PRIMARY

CAS

2093369-28-7

Created by admin on Sat Dec 16 20:11:44 GMT 2023 , Edited by admin on Sat Dec 16 20:11:44 GMT 2023

PRIMARY

FDA UNII

34FMX7983W

Created by admin on Sat Dec 16 20:11:44 GMT 2023 , Edited by admin on Sat Dec 16 20:11:44 GMT 2023

PRIMARY

Related Record Type Details


					WOH1JD9AR8

Olaparib

PARENT -> SALT/SOLVATE

Amount:


					WOH1JD9AR8

Olaparib

ANHYDROUS->SOLVATE

Amount:

Details

SMILES

InChI

DescriptionSources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdfCurator's Comment: Description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880823/

Originator

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Conditions

Approved Use

Launch Date

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AUC

T1/2

Funbound

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AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf
Curator's Comment: Description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880823/

C_max

T_1/2

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Drug as perpetrator