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=C(NC2=NC=CC(=N2)C3=CN(C)C4=CC=CC=C34)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C

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

Molecular Formula	C28H33N7O2
Molecular Weight	499.6073
Charge	0
Count

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

Molecular Formula	CH4O3S
Molecular Weight	96.106
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/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 46 Target ID: CHEMBL2363049 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf	Inhibitor 8297		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 8429	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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891183/pdf/CAS-109-1177.pdf	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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891183/pdf/CAS-109-1177.pdf	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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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 n = 411 Health Status: unhealthy Condition: EGFR T790M mutation-positive non-small cell lung cancer Age Group: 63 years Sex: M+F Population Size: 411 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 n = 1 Health Status: unhealthy Condition: EGFR L858R–mutant metastatic lung adenocarcinoma Age Group: 71 years Sex: F Population Size: 1 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 Page: 53	unhealthy n = 13 Health Status: unhealthy Condition: NSCLC Sex: M+F Population Size: 13 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf Page: 53	Other AEs: Rash, Diarrhea... Other AEs: Rash (60%) Diarrhea (58%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf Page: 53

AEs

Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 214 BCRP 699 CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2E1 882 P-gp 1461 OAT1 599 OAT3 642 OATP1B1 788 OATP1B3 706 MATE1 306 MATE2 263 OCT2 647 CYP2C8 911 CYP3A4/5 278 Cav1.2 45 Kv4.3 16 Kv1.5 26 Cav3.2 12	CYP3A 191 P-gp 1537 BCRP 561 OATP1B1 406 OATP1B3 350	CYP2C 15 P-gp 257 CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 22 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	no [IC50 22.8 uM]
MATE2 263	inhibitor 3277 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 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=54 Page: 54.0	no [IC50 31.91 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 4.63 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 52.5 uM]
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no [IC50 7.98 uM]
Kv1.5 41	inhibitor 3277 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 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=52 Page: 52.0	no [Inhibition 33 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=24 Page: 24.0	weak [IC50 5.1 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP2C 34	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
P-gp 1650	inducer 1573 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 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	major
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
P-gp 1537	substrate 3367 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 49	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000PharmR.pdf#page=51 Page: 51.0
hERG 1647	inhibitor 1626 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
		252160935
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.	2004 May 20	15118073
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.	2014 Sep	24893891
Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed.	2015 Dec	26522274
Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.	2015 Mar	25611025
The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC).	2015 May	26015938
Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer.	2015 Sep	26370354
Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer.	2015 Sep 1	26169963
Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches.	2016 Apr	26620497
Osimertinib: First Global Approval.	2016 Feb	26729184

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

Substance Class	Chemical Created by `admin` on `Sat Dec 16 05:18:41 GMT 2023` Edited by `admin` on `Sat Dec 16 05:18:41 GMT 2023`
Record UNII	RDL94R2A16
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

OSIMERTINIB MESYLATE

Official 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

OSIMERTINIB MESILATE

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

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