dabrafenib Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
Raf (Rapidely Accelerated Fibrosarcoma) kinase inhibitors	4801	1195765-45-7

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: GSK2118436B dabrafenib mesylate tafinlar dabrafenib GSK2118436 dabrafenib mesilate	Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo. Molecular weight: 519.56 Formula: C23H20F3N5O2S2 CLOGP: 4.61 LIPINSKI: 1 HAC: 7 HDO: 2 TPSA: 110.86 ALOGS: -5.20 ROTB: 5 Status: ONP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

GSK2118436B
dabrafenib mesylate
tafinlar
dabrafenib
GSK2118436
dabrafenib mesilate

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.

Molecular weight: 519.56
Formula: C23H20F3N5O2S2
CLOGP: 4.61
LIPINSKI: 1
HAC: 7
HDO: 2
TPSA: 110.86
ALOGS: -5.20
ROTB: 5

Status: ONP

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

Drug dosage:

None

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Hosey CM, Chan R, Benet LZ
Vd (Volume of distribution)	0.65 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	2.86 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.00 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	2.60 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
Aug. 26, 2013	EMA	Novartis Europharm Limited
May 29, 2013	FDA	NOVARTIS PHARMS CORP

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
Pyrexia	1194.90	21.03	814	9693	347988	46327567
Malignant neoplasm progression	564.82	21.03	280	10227	64646	46610909
Chills	306.98	21.03	217	10290	95815	46579740
Metastatic malignant melanoma	268.50	21.03	62	10445	1282	46674273
Uveitis	179.42	21.03	69	10438	8572	46666983
Malignant melanoma	171.52	21.03	70	10437	10164	46665391
Metastases to central nervous system	161.97	21.03	69	10438	11152	46664403
Death	143.65	21.03	264	10243	335284	46340271
Panniculitis	130.85	21.03	49	10458	5655	46669900
Malignant melanoma stage IV	104.37	21.03	17	10490	43	46675512
Ejection fraction decreased	103.42	21.03	59	10448	17878	46657677
Rash	84.11	21.03	221	10286	356291	46319264
Visual impairment	62.47	21.03	76	10431	66613	46608942
Dermatitis acneiform	58.61	21.03	25	10482	4045	46671510
Blood creatine phosphokinase increased	58.31	21.03	49	10458	27675	46647880
Drug ineffective	54.41	21.03	44	10463	677794	45997761
Erythema nodosum	50.40	21.03	22	10485	3764	46671791
Anaplastic thyroid cancer	46.13	21.03	8	10499	33	46675522
Chorioretinopathy	43.80	21.03	13	10494	728	46674827
Metastases to meninges	38.60	21.03	15	10492	1912	46673643
Vogt-Koyanagi-Harada disease	36.68	21.03	8	10499	126	46675429
Hyperpyrexia	36.58	21.03	16	10491	2750	46672805
Drug hypersensitivity	35.71	21.03	6	10501	243819	46431736
Metastasis	35.55	21.03	18	10489	4294	46671261
Iridocyclitis	34.58	21.03	14	10493	1986	46673569
Cutaneous sarcoidosis	33.81	21.03	9	10498	338	46675217
Serous retinal detachment	31.16	21.03	7	10500	127	46675428
Product use in unapproved indication	31.00	21.03	65	10442	90208	46585347
Hyperkeratosis	30.22	21.03	17	10490	5008	46670547
Rash maculo-papular	29.77	21.03	34	10473	27840	46647715
Vision blurred	29.26	21.03	59	10448	79649	46595906
Systemic inflammatory response syndrome	29.16	21.03	17	10490	5354	46670201
Erythema multiforme	28.73	21.03	21	10486	9683	46665872
Second primary malignancy	28.44	21.03	18	10489	6566	46668989
Squamous cell carcinoma	27.94	21.03	19	10488	7817	46667738
Vomiting	27.56	21.03	185	10322	452609	46222946
Metastases to lung	26.91	21.03	21	10486	10675	46664880
Skin toxicity	26.52	21.03	14	10493	3640	46671915
Retinal detachment	24.71	21.03	15	10492	5085	46670470
Myalgia	24.57	21.03	72	10435	123016	46552539
Pneumonitis	24.35	21.03	31	10476	28389	46647166
Dehydration	24.27	21.03	85	10422	159455	46516100
Blood lactate dehydrogenase increased	23.59	21.03	26	10481	20474	46655081
Off label use	23.18	21.03	31	10476	379810	46295745
Fall	23.14	21.03	24	10483	329073	46346482
Acute polyneuropathy	22.94	21.03	6	10501	210	46675345
Melanoma recurrent	22.79	21.03	5	10502	81	46675474
Nausea	22.26	21.03	244	10263	687210	45988345
Hepatocellular injury	21.89	21.03	30	10477	29492	46646063
Aspartate aminotransferase increased	21.77	21.03	52	10455	78648	46596907
Rhabdomyolysis	21.69	21.03	36	10471	41873	46633682
Astrocytoma	21.43	21.03	5	10502	108	46675447
C-reactive protein increased	21.06	21.03	43	10464	58547	46617008

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
Pyrexia	1133.19	20.22	921	10855	293568	29647134
Malignant neoplasm progression	559.12	20.22	349	11427	71938	29868764
Metastatic malignant melanoma	372.73	20.22	98	11678	1972	29938730
Chills	332.76	20.22	254	11522	72084	29868618
Metastases to central nervous system	320.49	20.22	117	11659	7167	29933535
Malignant melanoma	191.50	20.22	81	11695	7330	29933372
Ejection fraction decreased	168.71	20.22	93	11683	15082	29925620
Death	155.61	20.22	394	11382	356889	29583813
Uveitis	112.66	20.22	51	11725	5426	29935276
Metastases to liver	85.05	20.22	55	11721	11910	29928792
Malignant melanoma stage IV	81.13	20.22	15	11761	48	29940654
Metastases to stomach	71.07	20.22	14	11762	68	29940634
Basal cell carcinoma	70.44	20.22	55	11721	16013	29924689
Squamous cell carcinoma	62.90	20.22	43	11733	10207	29930495
Metastases to lung	57.85	20.22	37	11739	7858	29932844
Rash	56.00	20.22	184	11592	191705	29748997
Metastases to peritoneum	53.87	20.22	21	11755	1536	29939166
Second primary malignancy	52.13	20.22	32	11744	6324	29934378
C-reactive protein increased	51.68	20.22	74	11702	43399	29897303
Visual impairment	50.42	20.22	61	11715	30377	29910325
Blood creatine phosphokinase increased	49.73	20.22	73	11703	43775	29896927
Panniculitis	46.12	20.22	16	11760	841	29939861
Blood lactate dehydrogenase increased	45.58	20.22	48	11728	20553	29920149
Metastases to skin	45.22	20.22	13	11763	367	29940335
Metastases to meninges	44.43	20.22	17	11759	1182	29939520
Serous retinal detachment	43.44	20.22	12	11764	292	29940410
Procalcitonin increased	41.96	20.22	16	11760	1102	29939600
Chorioretinopathy	41.28	20.22	17	11759	1435	29939267
Hyperkeratosis	41.24	20.22	22	11754	3335	29937367
Malignant mesenteric neoplasm	39.78	20.22	8	11768	44	29940658
Jejunal ulcer perforation	36.55	20.22	8	11768	70	29940632
Off label use	36.42	20.22	27	11749	249263	29691439
Metastasis	36.03	20.22	20	11756	3278	29937424
Metastases to bone	35.84	20.22	30	11746	9628	29931074
Disease progression	35.26	20.22	89	11687	79785	29860917
Gastrointestinal wall thickening	33.92	20.22	13	11763	908	29939794
Erythema nodosum	33.53	20.22	13	11763	937	29939765
Metastases to lymph nodes	32.55	20.22	20	11756	3957	29936745
Tissue infiltration	31.51	20.22	7	11769	66	29940636
Haemophagocytic lymphohistiocytosis	31.43	20.22	28	11748	9763	29930939
Metastases to heart	31.40	20.22	8	11768	141	29940561
Intestinal metastasis	30.78	20.22	8	11768	153	29940549
Product use in unapproved indication	30.34	20.22	80	11696	73613	29867089
Eastern Cooperative Oncology Group performance status	30.31	20.22	6	11770	30	29940672
Omental necrosis	30.31	20.22	6	11770	30	29940672
Mesenteric neoplasm	29.99	20.22	6	11770	32	29940670
Anaplastic thyroid cancer	29.84	20.22	5	11771	7	29940695
Ureteral disorder	29.77	20.22	8	11768	175	29940527
Hyperpyrexia	29.18	20.22	16	11760	2561	29938141
Brain neoplasm	28.06	20.22	16	11760	2761	29937941
Drug interaction	27.37	20.22	23	11753	199545	29741157
Fatigue	26.17	20.22	215	11561	320458	29620244
Toxicity to various agents	26.09	20.22	19	11757	177164	29763538
Drug ineffective	25.93	20.22	60	11716	340327	29600375
Body temperature fluctuation	23.53	20.22	11	11765	1258	29939444
Decreased appetite	23.00	20.22	118	11658	149792	29790910
Inflammatory bowel disease	22.60	20.22	13	11763	2280	29938422
Small intestine carcinoma	22.59	20.22	8	11768	447	29940255
Iridocyclitis	22.43	20.22	11	11765	1398	29939304
Papilloedema	22.27	20.22	13	11763	2343	29938359
Leukoderma	21.64	20.22	5	11771	57	29940645
Abdominal lymphadenopathy	21.26	20.22	8	11768	531	29940171
Tumour invasion	20.78	20.22	7	11769	336	29940366
Anxiety	20.60	20.22	5	11771	89866	29850836
BRAF V600E mutation positive	20.56	20.22	4	11772	18	29940684
Metastases to adrenals	20.31	20.22	9	11767	909	29939793

Pharmacologic Action:

Source	Code	Description
ATC	L01EC02	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS PROTEIN KINASE INHIBITORS B-Raf serine-threonine kinase (BRAF) inhibitors
FDA MoA	N0000175076	Protein Kinase Inhibitors
FDA EPC	N0000175605	Kinase Inhibitor
MeSH PA	D000970	Antineoplastic Agents
MeSH PA	D004791	Enzyme Inhibitors
MeSH PA	D047428	Protein Kinase Inhibitors
FDA MoA	N0000185506	Cytochrome P450 3A4 Inducers
FDA MoA	N0000185507	Cytochrome P450 2C9 Inducers
FDA MoA	N0000185607	Cytochrome P450 2C19 Inducers
FDA MoA	N0000187063	Cytochrome P450 2C8 Inducers
FDA MoA	N0000187064	Cytochrome P450 2B6 Inducers
FDA MoA	N0000190107	Organic Anion Transporting Polypeptide 1B1 Inhibitors
FDA MoA	N0000190108	Organic Anion Transporting Polypeptide 1B3 Inhibitors
FDA MoA	N0000190110	Organic Anion Transporter 1 Inhibitors
FDA MoA	N0000190111	Organic Anion Transporter 3 Inhibitors
FDA MoA	N0000190113	Breast Cancer Resistance Protein Inhibitors
CHEBI has role	CHEBI:35610	cytostatic
CHEBI has role	CHEBI:75047	b-raf inhibitors
CHEBI has role	CHEBI:149553	anti-coronaviral agents

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Metastatic malignant melanoma	indication	443493003
Malignant Melanoma with BRAF V600E Mutation	indication

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	8.56	acidic
pKa2	3.35	Basic
pKa3	0.43	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	Jan. 9, 2021	DABRAFENIB IN COMBO WITH TRAMETINIB FOR TX. OF PTS WITH UNRESECTABLE OR METASTATIC MELANOMA WITH BRAF V600E OR V600K MUTATIONS AS DETECTED BY AN FDA-APPROVED TEST. THIS INDICATION IS BASED ON THE DEMONSTRATION OF DURABLE RESPONSE RATE
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	Jan. 9, 2021	DABRAFENIB IN COMBO WITH TRAMETINIB FOR TX. OF PTS WITH UNRESECTABLE OR METASTATIC MELANOMA WITH BRAF V600E OR V600K MUTATIONS AS DETECTED BY AN FDA-APPROVED TEST. THIS INDICATION IS BASED ON THE DEMONSTRATION OF DURABLE RESPONSE RATE
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	April 30, 2021	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB FOR THE ADJUVANT TREATMENT OF PATIENTS WITH MELANOMA WITH BRAF V600E OR V600K MUTATIONS, AS DETECTED BY AN FDA-APPROVED TEST, AND INVOLVEMENT OF LYMPH NODE(S), FOLLOWING COMPLETE RESECTION
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	April 30, 2021	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB FOR THE ADJUVANT TREATMENT OF PATIENTS WITH MELANOMA WITH BRAF V600E OR V600K MUTATIONS, AS DETECTED BY AN FDA-APPROVED TEST, AND INVOLVEMENT OF LYMPH NODE(S), FOLLOWING COMPLETE RESECTION
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	May 4, 2021	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC ANULLPLASTIC THYROID CANCER (ATC) WITH BRAF V600E MUTATION AND WITH NO SATISFACTORY LOCOREGIONULLL TREATMENT OPTIONS
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	May 4, 2021	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC ANULLPLASTIC THYROID CANCER (ATC) WITH BRAF V600E MUTATION AND WITH NO SATISFACTORY LOCOREGIONULLL TREATMENT OPTIONS
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	Oct. 6, 2022	ADDITION OF STUDY BRF117277, A NON-RANDOMIZED, OPEN-LABEL, MULTI-CENTER, MULTI-COHORT TRIAL OF DABRAFENIB PLUS TRAMETINIB IN SUBJECTS WITH BRAF MUTATION-POSITIVE MELANOMA THAT HAS METASTASIZED TO THE BRAIN
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	Oct. 6, 2022	ADDITION OF STUDY BRF117277, A NON-RANDOMIZED, OPEN-LABEL, MULTI-CENTER, MULTI-COHORT TRIAL OF DABRAFENIB PLUS TRAMETINIB IN SUBJECTS WITH BRAF MUTATION-POSITIVE MELANOMA THAT HAS METASTASIZED TO THE BRAIN
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	June 22, 2024	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB, FOR THE TX. OF PTS WITH METASTATIC NON-SMALL CELL LUNG CANCER WITH BRAF V600E MUTATION AS DETECTED BY AN FDA-APPROVED TEST
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	June 22, 2024	DABRAFENIB IN COMBINULLTION WITH TRAMETINIB, FOR THE TX. OF PTS WITH METASTATIC NON-SMALL CELL LUNG CANCER WITH BRAF V600E MUTATION AS DETECTED BY AN FDA-APPROVED TEST
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	April 30, 2025	TRAMETINIB IS INDICATED, IN COMBINULLTION WITH DABRAFENIB, FOR THE ADJUVANT TREATMENT OF PATIENTS WITH MELANOMA WITH BRAF V600E OR V600K MUTATIONS, AS DETECTED BY AN FDA-APPROVED TEST, AND INVOLVEMENT OF LYMPH NODE(S), FOLLOWING COMPLETE RESECTION
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	April 30, 2025	TRAMETINIB IS INDICATED, IN COMBINULLTION WITH DABRAFENIB, FOR THE ADJUVANT TREATMENT OF PATIENTS WITH MELANOMA WITH BRAF V600E OR V600K MUTATIONS, AS DETECTED BY AN FDA-APPROVED TEST, AND INVOLVEMENT OF LYMPH NODE(S), FOLLOWING COMPLETE RESECTION
EQ 50MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	May 4, 2025	TRAMETINIB AND DABRAFENIB IN COMBINULLTION, FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC ANULLPLASTIC THYROID CANCER (ATC) WITH BRAF V600E MUTATION AND WITH NO SATISFACTORY LOCOREGIONULLL TREATMENT OPTIONS
EQ 75MG BASE	TAFINLAR	NOVARTIS	N202806	May 29, 2013	RX	CAPSULE	ORAL	May 4, 2025	TRAMETINIB AND DABRAFENIB IN COMBINULLTION, FOR THE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC ANULLPLASTIC THYROID CANCER (ATC) WITH BRAF V600E MUTATION AND WITH NO SATISFACTORY LOCOREGIONULLL TREATMENT OPTIONS

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Serine/threonine-protein kinase B-raf	Kinase	P15056	BRAF_HUMAN	INHIBITOR	IC50	9.15	WOMBAT-PK	CHEMBL
TGF-beta receptor type-1	Kinase	P36897	TGFR1_HUMAN		IC50	5.43	CHEMBL
RAF proto-oncogene serine/threonine-protein kinase	Kinase	P04049	RAF1_HUMAN		IC50	6.82	CHEMBL
Serine/threonine-protein kinase A-Raf	Kinase	P10398	ARAF_HUMAN		IC50	7.59	CHEMBL

External reference:

ID	Source
D10064	KEGG_DRUG
1195768-06-9	SECONDARY_CAS_RN
4032496	VANDF
C3467876	UMLSCUI
CHEBI:75045	CHEBI
P06	PDB_CHEM_ID
CHEMBL2028663	ChEMBL_ID
CHEMBL2105729	ChEMBL_ID
DB08912	DRUGBANK_ID
C561627	MESH_SUPPLEMENTAL_RECORD_UI
44462760	PUBCHEM_CID
6494	IUPHAR_LIGAND_ID
9458	INN_ID
QGP4HA4G1B	UNII
1424911	RXNORM
203107	MMSL
29476	MMSL
29650	MMSL
d08103	MMSL
015042	NDDF
015043	NDDF
703641001	SNOMEDCT_US
703642008	SNOMEDCT_US
703646006	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Tafinlar	HUMAN PRESCRIPTION DRUG LABEL	1	0078-0681	CAPSULE	75 mg	ORAL	NDA	32 sections
Tafinlar	HUMAN PRESCRIPTION DRUG LABEL	1	0078-0682	CAPSULE	50 mg	ORAL	NDA	32 sections