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brigatinib 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
tyrosine kinase inhibitors	5233	1197953-54-0

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: brigatinib alunbrig AP26113	Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice. At clinically achievable concentrations (<= 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line. Molecular weight: 584.10 Formula: C29H39ClN7O2P CLOGP: 2.08 LIPINSKI: 1 HAC: 9 HDO: 2 TPSA: 85.86 ALOGS: -4.42 ROTB: 8 Status: ONP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

brigatinib
alunbrig
AP26113

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice. At clinically achievable concentrations (<= 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

Molecular weight: 584.10
Formula: C29H39ClN7O2P
CLOGP: 2.08
LIPINSKI: 1
HAC: 9
HDO: 2
TPSA: 85.86
ALOGS: -4.42
ROTB: 8

Status: ONP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
0.18	g	O

ADMET properties:

Property	Value	Reference
S (Water solubility)	0.15 mg/mL	Bocci G, Oprea TI, Benet LZ
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Bocci G, Oprea TI, Benet LZ

Approvals:

Date	Agency	Company
Sept. 22, 2018	EMA	TAKEDA PHARMA A/S
April 28, 2017	FDA	ARIAD
Jan. 22, 2021	PMDA	TAKEDA PHARMACEUTICAL COMPANY LIMITED

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Neoplasm progression	184.03	31.27	61	1919	36367	63450675
Blood creatine phosphokinase increased	178.19	31.27	57	1923	30373	63456669
Metastases to central nervous system	162.77	31.27	44	1936	13061	63473981
Product dose omission issue	52.00	31.27	49	1931	234264	63252778
Amylase increased	50.18	31.27	15	1965	6330	63480712
Death	39.29	31.27	53	1927	374328	63112714
Drug resistance	37.65	31.27	17	1963	22916	63464126
Lipase increased	35.97	31.27	13	1967	9887	63477155
Disease progression	35.77	31.27	30	1950	122728	63364314

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Blood creatine phosphokinase increased	115.89	36.29	47	1158	44810	34910916
Neoplasm progression	102.22	36.29	36	1169	23264	34932462
Metastases to central nervous system	74.27	36.29	22	1183	8183	34947543
Death	41.65	36.29	59	1146	397990	34557736
Amylase increased	37.06	36.29	12	1193	5956	34949770

FDA Adverse Event Reporting System (Geriatric)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Blood creatine phosphokinase increased	257.58	30.91	93	2602	65997	79675696
Metastases to central nervous system	180.73	30.91	51	2644	16324	79725369
Neoplasm progression	172.58	30.91	65	2630	51617	79690076
Amylase increased	93.00	30.91	28	2667	11181	79730512
Disease progression	62.83	30.91	51	2644	184311	79557382
Lipase increased	52.26	30.91	20	2675	16446	79725247
Death	49.94	30.91	77	2618	566437	79175256
Product dose omission issue	48.08	30.91	50	2645	247487	79494206
Metastases to liver	48.01	30.91	22	2673	28292	79713401
Diarrhoea	41.19	30.91	91	2604	880398	78861295
Non-small cell lung cancer	36.51	30.91	12	2683	6348	79735345
Pulmonary toxicity	35.03	30.91	14	2681	12900	79728793
Drug resistance	31.68	30.91	19	2676	42194	79699499

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

Source	Code	Description
ATC	L01ED04	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS PROTEIN KINASE INHIBITORS Anaplastic lymphoma kinase (ALK) inhibitors
FDA MoA	N0000020001	Tyrosine Kinase Inhibitors
FDA EPC	N0000175605	Kinase Inhibitor
FDA MoA	N0000190118	Cytochrome P450 3A Inducers

Drug Use | Suggest Off label Use Form| |View source of the data|

Disease	Relation	SNOMED_ID	DOID
Non-small cell lung cancer	indication	254637007	DOID:3908
Advanced/recurrent anaplasticlymphoma kinase (ALK)-positive non-small cell lung cancer	indication	830151004

🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	8.76	Basic
pKa2	5.51	Basic
pKa3	4.76	Basic
pKa4	2.49	Basic

Orange Book patent data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent use
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	9273077	May 21, 2029	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	9273077	May 21, 2029	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	9273077	May 21, 2029	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	9611283	April 10, 2034	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	9611283	April 10, 2034	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	9611283	April 10, 2034	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	10385078	Nov. 10, 2035	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	10385078	Nov. 10, 2035	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	10385078	Nov. 10, 2035	TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)

Orange Book exclusivity data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	May 22, 2023	EXPANDED INDICATION OF THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	May 22, 2023	EXPANDED INDICATION OF THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	May 22, 2023	EXPANDED INDICATION OF THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	April 28, 2024	TREATMENT OF PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	April 28, 2024	TREATMENT OF PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	April 28, 2024	TREATMENT OF PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB
180MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	Oct. 2, 2017	RX	TABLET	ORAL	May 22, 2027	FOR THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST, NOT INCLUDING PATIENTS WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB
30MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	May 22, 2027	FOR THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST, NOT INCLUDING PATIENTS WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB
90MG	ALUNBRIG	TAKEDA PHARMS USA	N208772	April 28, 2017	RX	TABLET	ORAL	May 22, 2027	FOR THE TREATMENT OF ADULT PATIENTS WITH ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AS DETECTED BY AN FDA-APPROVED TEST, NOT INCLUDING PATIENTS WHO HAVE PROGRESSED ON OR ARE INTOLERANT TO CRIZOTINIB

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
ALK tyrosine kinase receptor	Kinase	Q9UM73	ALK_HUMAN	INHIBITOR	IC50	9.22	SCIENTIFIC LITERATURE	DRUG LABEL
Epidermal growth factor receptor	Kinase	P00533	EGFR_HUMAN	INHIBITOR	IC50	7.17	SCIENTIFIC LITERATURE
Receptor-type tyrosine-protein kinase FLT3	Kinase	P36888	FLT3_HUMAN	INHIBITOR	IC50	8.68	SCIENTIFIC LITERATURE
NUAK family SNF1-like kinase 1	Kinase	O60285	NUAK1_HUMAN		IC50	7.33	CHEMBL
Insulin receptor	Kinase	P06213	INSR_HUMAN	INHIBITOR	IC50	6.80	SCIENTIFIC LITERATURE
Proto-oncogene tyrosine-protein kinase ROS	Kinase	P08922	ROS1_HUMAN	INHIBITOR	IC50	8.72	SCIENTIFIC LITERATURE
Insulin-like growth factor 1 receptor	Kinase	P08069	IGF1R_HUMAN	INHIBITOR	IC50	7.14	SCIENTIFIC LITERATURE

External reference:

ID	Source
HYW8DB273J	UNII
4036651	VANDF
C4287815	UMLSCUI
6GY	PDB_CHEM_ID
CHEMBL3545311	ChEMBL_ID
68165256	PUBCHEM_CID
DB12267	DRUGBANK_ID
D10866	KEGG_DRUG
10085	INN_ID
7741	IUPHAR_LIGAND_ID
256904	MMSL
32700	MMSL
d08581	MMSL
017195	NDDF
736634002	SNOMEDCT_US
763704002	SNOMEDCT_US
1921217	RXNORM
C000598580	MESH_SUPPLEMENTAL_RECORD_UI

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-090	TABLET, FILM COATED	90 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-090	TABLET, FILM COATED	90 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-090	TABLET, FILM COATED	90 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-090	TABLET, FILM COATED	90 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-113	TABLET, FILM COATED	30 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-113	TABLET, FILM COATED	30 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-113	TABLET, FILM COATED	30 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-113	TABLET, FILM COATED	30 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-180	TABLET, FILM COATED	180 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-180	TABLET, FILM COATED	180 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-180	TABLET, FILM COATED	180 mg	ORAL	NDA	31 sections
Alunbrig	HUMAN PRESCRIPTION DRUG LABEL	1	63020-180	TABLET, FILM COATED	180 mg	ORAL	NDA	31 sections