OSIMERTINIB MESYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H33N7O2.CH4O3S
Molecular Weight	595.713
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC2=NC(=CC=N2)C3=CN(C)C4=C3C=CC=C4

InChI

InChIKey=FUKSNUHSJBTCFJ-UHFFFAOYSA-N

InChI=1S/C28H33N7O2.CH4O3S/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24;1-5(2,3)4/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32);1H3,(H,2,3,4)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB09330

Osimertinib is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals. Its use is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in cases where tumour EGFR expression is positive for the T790M mutation as detected by FDA-approved testing and which has progressed following therapy with a first-generation EGFR tyrosine kinase inhibitor. Approximately 10% of patients with NSCLC have a rapid and clinically effective response to EGFR-TKIs due to the presence of specific activating EGFR mutations within the tumour cells. More specifically, deletions around the LREA motif in exon 19 and exon 21 L858R point mutations are correlated with response to therapy. Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity. Osimertinib is marketed under the brand name Tagrisso.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Epidermal growth factor receptor 49 Target ID: CHEMBL2363049 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf	Inhibitor 8504		12.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Metastatic EGFR T790M mutation positive non-small cell lung cancer 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf	Primary		Approved 8583	TAGRISSO Approved Use TAGRISSO is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non-small cell lung cancer (NSCLC), as detected by an FDA approved test, who have progressed on or after EGFR TKI therapy. Launch Date 2015

C_max

Value	Dose	Co-administered	Analyte	Population
660.7 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29363250/	80 mg 1 times / day steady-state, oral dose: 80 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OSIMERTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
118 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29683562/	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		OSIMERTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
12670 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29363250/	80 mg 1 times / day steady-state, oral dose: 80 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OSIMERTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6770 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29683562/	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		OSIMERTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
59.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29683562/	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		OSIMERTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf			OSIMERTINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
80 mg 1 times / day steady, oral Recommended Dose: 80 mg, 1 times / day Route: oral Route: steady Dose: 80 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf	unhealthy, 63 years Health Status: unhealthy Age Group: 63 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf	Disc. AE: Electrocardiogram QT prolonged, Neutropenia... Other AEs: Diarrhea, Diarrhea... AEs leading to discontinuation/dose reduction: Electrocardiogram QT prolonged (2.2%) Neutropenia (1.9%) Pneumonitis (grade 5, 1%) Pneumonia (grade 5, 4 patients) Cerebral hemorrhage (grade 5, 2 patients) Other AEs: Diarrhea (grade 1-2, 41%) Diarrhea (grade 3-4, 1%) Nausea (grade 1-2, 16.5%) Nausea (grade 3-4, 0.5%) Decreased appetite (grade 1-2, 15.3%) Decreased appetite (grade 3-4, 0.7%) Constipation (grade 1-2, 14.8%) Constipation (grade 3-4, 0.2%) Stomatitis (grade 1-2, 12%) Rash (grade 1-2, 40.5%) Generalized rash (grade 1-2, 40.5%) Rash erythematous (grade 1-2, 40.5%) Rash macular (grade 1-2, 40.5%) Rash maculo-papular (grade 1-2, 40.5%) Rash papular (grade 1-2, 40.5%) Rash pustular (grade 1-2, 40.5%) Erythema (grade 1-2, 40.5%) Folliculitis (grade 1-2, 40.5%) Acne (grade 1-2, 40.5%) Dermatitis (grade 1-2, 40.5%) Acneiform dermatitis (grade 1-2, 40.5%) Rash (grade 3-4, 0.5%) Generalized rash (grade 3-4, 0.5%) Rash erythematous (grade 3-4, 0.5%) Rash macular (grade 3-4, 0.5%) Rash maculo-papular (grade 3-4, 0.5%) Rash papular (grade 3-4, 0.5%) Rash pustular (grade 3-4, 0.5%) Erythema (grade 3-4, 0.5%) Folliculitis (grade 3-4, 0.5%) Acne (grade 3-4, 0.5%) Dermatitis (grade 3-4, 0.5%) Acneiform dermatitis (grade 3-4, 0.5%) Dry skin (grade 1-2, 31%) Eczema (grade 1-2, 31%) Skin fissures (grade 1-2, 31%) Xerosis (grade 1-2, 31%) Disorder nail (grade 1-2, 25%) Nail bed disorder (grade 1-2, 25%) Nail bed inflammation (grade 1-2, 25%) Nail bed tenderness (grade 1-2, 25%) Nail discoloration (grade 1-2, 25%) Nail dystrophy (grade 1-2, 25%) Nail infection (grade 1-2, 25%) Nail ridging (grade 1-2, 25%) Onychoclasis (grade 1-2, 25%) Onycholysis (grade 1-2, 25%) Onychomadesis (grade 1-2, 25%) Paronychia (grade 1-2, 25%) Pruritus (grade 1-2, 14%) Cough (grade 1-2, 13.8%) Cough (grade 3-4, 0.2%) Fatigue (grade 1-2, 13.5%) Fatigue (grade 3-4, 0.5%) Back pain (grade 1-2, 12.3%) Back pain (grade 3-4, 0.7%) Headache (grade 1-2, 9.8%) Headache (grade 3-4, 0.2%) Pneumonia (grade 1-2, 1.8%) Pneumonia (grade 3-4, 2.2%) Deep vein thrombosis (grade 1-2, 4.6%) Jugular vein thrombosis (grade 1-2, 4.6%) Pulmonary embolism (grade 1-2, 4.6%) Deep vein thrombosis (grade 3-4, 2.4%) Jugular vein thrombosis (grade 3-4, 2.4%) Pulmonary embolism (grade 3-4, 2.4%) Cerebrovascular accident (2.7%) Hyponatremia (grade 1-2, 22.6%) Hyponatremia (grade 3-4, 3.4%) Hypermagnesemia (grade 1-2, 19.3%) Hypermagnesemia (grade 3-4, 0.7%) Lymphopenia (grade 1-2, 59.7%) Lymphopenia (grade 3-4, 3.3%) Thrombocytopenia (grade 1-2, 52.8%) Thrombocytopenia (grade 3-4, 1.2%) Anemia (grade 1-2, 43.8%) Anemia (grade 3-4, 0.2%) Neutropenia (grade 1-2, 29.6%) Neutropenia (grade 3-4, 3.4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
240 mg 1 times / day multiple, oral Highest studied dose Dose: 240 mg, 1 times / day Route: oral Route: multiple Dose: 240 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29074213	unhealthy, 71 years Health Status: unhealthy Age Group: 71 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/29074213	Other AEs: Nausea, Vomiting... Other AEs: Nausea Vomiting Diarrhea Sources: https://pubmed.ncbi.nlm.nih.gov/29074213
240 mg 1 times / day steady, oral Highest studied dose Dose: 240 mg, 1 times / day Route: oral Route: steady Dose: 240 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf	unhealthy Health Status: unhealthy Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf	Other AEs: Rash, Diarrhea... Other AEs: Rash (60%) Diarrhea (58%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 BCRP 910 CYP1A2 2153 CYP2A6 879 CYP2B6 926 CYP2E1 1060 P-gp 1741 OAT1 725 OAT3 747 OATP1B1 1079 OATP1B3 961 MATE1 415 MATE2 267 OCT2 779 CYP2C8 1057 CYP3A4/5 296 Cav1.2 58 Kv4.3 16 Kv1.5 27 Cav3.2 12	CYP3A 220 P-gp 2052 BCRP 697 OATP1B1 503 OATP1B3 435	CYP2C 17 P-gp 301 CYP1A2 832

Drug as perpetrator

Target	Modality	Activity
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 22 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	no [IC50 22.8 uM]
MATE2 267	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 23 uM]
Cav3.2 12	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=54 Page: 54.0	no [IC50 31.91 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 4.63 uM]
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 52.5 uM]
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 7.98 uM]
Kv1.5 42	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=54 Page: 54.0	no [IC50 >100 uM]
Kv4.3 16	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=52 Page: 52.0	no [Inhibition 33 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	weak [IC50 5.1 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP2C 37	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP3A 317	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
P-gp 1932	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes

Drug as victim

Target	Modality	Activity
CYP3A 220	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	major
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 63	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=51 Page: 51.0
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=53 Page: 53.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90943	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90943
ChemicalBook	CB02677059	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02677059
MolPort	MolPort-035-395-886	https://www.molport.com/shop/molecule-link/MolPort-035-395-886
ZINC	ZINC000098023177	http://zinc15.docking.org/substances/ZINC000098023177

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

80 mg orally once daily, with or without food

Route of Administration: Oral

In Vitro Use Guide

Osimertinib inhibited cell lines harboring classic EGFR mutations, exon 19 deletions (PC-9) and L858R (H3255) with IC50 values 17 nM and 4 nM, respectively

Name

Type

Language

OSIMERTINIB MESYLATE

Official Name

English

OSIMERTINIB MESILATE

Preferred Name

English

Osimertinib mesilate [WHO-DD]

Common Name

English

OSIMERTINIB MESILATE [JAN]

Common Name

English

MERELETINIB MESILATE

Common Name

English

OSIMERTINIB MESYLATE [USAN]

Common Name

English

2-PROPENAMIDE, N-(2-((2-(DIMETHYLAMINO)ETHYL)METHYLAMINO)-4-METHOXY-5-((4-(1-METHYL-1H-INDOL-3-YL)-2-PYRIMIDINYL)AMINO)PHENYL)-, METHANESULFONATE (1:1)

Systematic Name

English

OSIMERTINIB MESYLATE [MI]

Common Name

English

OSIMERTINIB MESYLATE [ORANGE BOOK]

Common Name

English

TAGRISSO

Brand Name

English

AZD-9291 MESYLATE

Code

English

AZD9291 MESYLATE

Code

English

MERELETINIB MESYLATE

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

TAGRISSO (AUTHORISED: CARCINOMA, NON-SMALL-CELL LUNG)