DABRAFENIB MESYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H20F3N5O2S2.CH4O3S
Molecular Weight	615.668
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.CC(C)(C)C1=NC(=C(S1)C2=NC(N)=NC=C2)C3=CC=CC(NS(=O)(=O)C4=C(F)C=CC=C4F)=C3F

InChI

InChIKey=YKGMKSIHIVVYKY-UHFFFAOYSA-N

InChI=1S/C23H20F3N5O2S2.CH4O3S/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25;1-5(2,3)4/h4-11,31H,1-3H3,(H2,27,28,29);1H3,(H,2,3,4)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202806s005lbl.pdf

Dabrafenib is a selective, orally bioavailable inhibitor of Mutant BRAF protein kinase with potential antineoplastic activity. Dabrafenib inhibits 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. BRAF belongs to the the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations. Mutations in BRAF are associated with increased growth and proliferation of cancer cells. By inhibiting BRAF kinase dabrafenib negatively regulates the proliferation of tumor cells which contain a mutated BRAF gene. Dabrafenib (in combination with trametinib or alone) is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase B-raf 20 Target ID: P15056\|\|\|Q13878 Gene ID: 673.0 Gene Symbol: BRAF Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202806s005lbl.pdf	Inhibitor 8297		3.2 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Melanoma 88 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202806s005lbl.pdf	Primary		Approved 8429	TAFINLAR Approved Use Indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test; in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. Limitation of Use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. Launch Date 2013

C_max

Value	Dose	Co-administered	Analyte	Population
2497.4 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947742/pdf/JDE-45-397.pdf	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: TRAMETINIB	TRAMETINIB	DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
806 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1478 ng/mL OTHER GOV https://www.ema.europa.eu/en/documents/product-information/tafinlar-epar-product-information_en.pdf	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
13485.6 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947742/pdf/JDE-45-397.pdf	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: TRAMETINIB	TRAMETINIB	DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2619 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4341 μg × h/mL OTHER GOV https://www.ema.europa.eu/en/documents/product-information/tafinlar-epar-product-information_en.pdf	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947742/pdf/JDE-45-397.pdf	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered: TRAMETINIB	TRAMETINIB	DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.2 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	300 mg 2 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8 h OTHER GOV https://www.ema.europa.eu/en/documents/product-information/tafinlar-epar-product-information_en.pdf	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.3% OTHER GOV https://www.ema.europa.eu/en/documents/product-information/tafinlar-epar-product-information_en.pdf	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DABRAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 94	unhealthy, 53 years (range: 22-93 years) n = 187 Health Status: unhealthy Age Group: 53 years (range: 22-93 years) Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 94	Disc. AE: Constipation, Hepatic pain... AEs leading to discontinuation/dose reduction: Constipation (serious, 1 patient) Hepatic pain (serious, 1 patient) Myocardial infarction (serious, 1 patient) Tricuspid valve disease (2 patients) Muscular weakness (serious, 2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 94
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 96	unhealthy, 53 years (range: 22-93 years) n = 187 Health Status: unhealthy Age Group: 53 years (range: 22-93 years) Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 96	Disc. AE: Pain, Hyperkeratosis... AEs leading to discontinuation/dose reduction: Pain (1%) Hyperkeratosis (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 96
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 97	unhealthy, 53 years (range: 22-93 years) n = 187 Health Status: unhealthy Age Group: 53 years (range: 22-93 years) Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 97	Disc. AE: Hyperhidrosis, Migraine... AEs leading to discontinuation/dose reduction: Hyperhidrosis (1%) Migraine (1%) Syncope (1%) Vomiting (1%) Diarrhea (1%) Nausea (1%) Atrial fibrillation (1%) Alanine aminotransferase increased (1%) Aspartate aminotransferase increased (1%) Diabetes mellitus (1%) Diabetes mellitus inadequate control (1%) Pulmonary edema (1%) Respiratory distress (1%) Pleural effusion (1%) Alkaline phosphatase increased (1%) Ejection fraction decreased (1%) Gamma-glutamyltransferase increased (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 97
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 98	unhealthy, 53 years (range: 22-93 years) n = 187 Health Status: unhealthy Age Group: 53 years (range: 22-93 years) Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 98	Disc. AE: Oropharyngeal pain, Malaise... AEs leading to discontinuation/dose reduction: Oropharyngeal pain (1%) Malaise (1%) Small intestinal perforation (1%) Neutropenia (1%) Thrombocytopenia (1%) Cataract (1%) Gastrointestinal infection (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 98
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 99	unhealthy, 53 years (range: 22-93 years) n = 187 Health Status: unhealthy Age Group: 53 years (range: 22-93 years) Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 99	Disc. AE: Back pain, Muscle spasms... AEs leading to discontinuation/dose reduction: Back pain (1%) Muscle spasms (1%) Musculoskeletal stiffness (1%) Pemphigoid (1%) Hyperkeratosis (1%) Urinary bladder polyp (1%) Urinary retention (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 99
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	unhealthy, 53 years n = 187 Health Status: unhealthy Condition: unresectable or metastatic melanoma with BRAF V600E mutation-positive melanoma Age Group: 53 years Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	Disc. AE: Pyrexia, Pyrexia... AEs leading to discontinuation/dose reduction: Pyrexia (all grades, 28%) Pyrexia (grade 3-4, 3%) Fatigue (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	unhealthy, 53 years n = 187 Health Status: unhealthy Condition: unresectable or metastatic melanoma with BRAF V600E mutation-positive melanoma Age Group: 53 years Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	Disc. AE: Constipation, Constipation... AEs leading to discontinuation/dose reduction: Constipation (all grades, 11%) Constipation (grade 3-4, 2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	unhealthy, 53 years n = 187 Health Status: unhealthy Condition: unresectable or metastatic melanoma with BRAF V600E mutation-positive melanoma Age Group: 53 years Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf	Disc. AE: Back pain, Back pain... AEs leading to discontinuation/dose reduction: Back pain (all grades, 12%) Back pain (grade 3-4, 3%) Myalgia (all grades, 11%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf	unhealthy, 53 years n = 187 Health Status: unhealthy Condition: unresectable or metastatic melanoma with BRAF V600E mutation-positive melanoma Age Group: 53 years Sex: M+F Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf	Disc. AE: Squamous cell carcinoma of skin, Keratoacanthoma... Other AEs: Hyperkeratosis, Hyperkeratosis... AEs leading to discontinuation/dose reduction: Squamous cell carcinoma of skin (grade 3-4, 4%) Keratoacanthoma (grade 3-4, 4%) Headache (all grades, 32%) Arthralgia (all grades, 27%) Arthralgia (grade 3-4, 1%) Chills (3%) Palmar-plantar erythrodysesthesia syndrome (3%) Hypophosphatemia (37%) Hypophosphatemia (6%) Pancreatitis (<10%) Other AEs: Hyperkeratosis (all grades, 37%) Hyperkeratosis (grade 3-4, 1%) Alopecia (all grades, 22%) Palmar-plantar erythrodysesthesia syndrome (all grades, 20%) Palmar-plantar erythrodysesthesia syndrome (grade 3-4, 2%) Rash (all grades, 17%) Papilloma (all grades, 27%) Cough (all grades, 12%) Nasopharyngitis (all grades, 10%) Hyperglycemia (all grades, 50%) Hyperglycemia (grade 3-4, 6%) Alkaline phosphatase increased (19%) Hyponatremia (8%) Hyponatremia (2%) Bullous rash (<10%) Nephritis interstitial (<10%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf
100 mg 3 times / day multiple, oral Highest studied dose Dose: 100 mg, 3 times / day Route: oral Route: multiple Dose: 100 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24958809	unhealthy n = 20 Health Status: unhealthy Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/24958809	Other AEs: Squamous cell carcinoma of skin, Pyrexia... Other AEs: Squamous cell carcinoma of skin (grade 3, 25%) Pyrexia (grade 2, 5%) Sources: https://pubmed.ncbi.nlm.nih.gov/24958809
300 mg 2 times / day multiple, oral Highest studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	unhealthy n = 10 Health Status: unhealthy Sex: M+F Population Size: 10 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	DLT: Hyponatraemia, Squamous cell carcinoma of skin... Dose limiting toxicities: Hyponatraemia (grade 4, 1 patient) Squamous cell carcinoma of skin (grade 3, 1 patient) Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 95	unhealthy n = 187 Health Status: unhealthy Population Size: 187 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 95	Disc. AE: Pancytopenia, Lymphocytopenia... AEs leading to discontinuation/dose reduction: Pancytopenia (2 patients) Lymphocytopenia (1 patient) Infarct myocardial (grade 5, 1 patient) Acute coronary syndrome (grade 5, 1 patient) Heart attack (1 patient) Abdominal pain (severe, 1 patient) Glissonitis (1 patient) Creatinine increased (1 patient) Epileptic seizure (1 patient) Cerebral hemorrhage (grade 5, 1 patient) Hyponatremia (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000MedR.pdf Page: p. 95
200 mg 2 times / day multiple, oral Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	unhealthy n = 20 Health Status: unhealthy Sex: M+F Population Size: 20 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/	DLT: Squamous cell carcinoma of skin, Syncope... Dose limiting toxicities: Squamous cell carcinoma of skin (grade 3, 1 patient) Syncope (grade 3, 1 patient) Pyrexia (grade 2, 1 patient) Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109288/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781 inhibitor 1587	substrate 1037 inhibitor 1767		inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 CYP2C19 1478 CYP1A2 1524 BCRP 699 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 P-gp 1461	CYP2C8 693 CYP2C19 991 P-gp 1537	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=25 Page: -	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=28 Page: -	yes [IC50 1.4 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=26 Page: -	yes [IC50 16 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=26 Page: -	yes [IC50 22 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=29 Page: -	yes [IC50 3.4 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=28 Page: -	yes [IC50 4.7 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -	yes [IC50 5.4 uM]
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=29 Page: -	yes [IC50 6.9 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=26 Page: -	yes [IC50 7.2 uM]	unknown (co-administration study) Comment: A study (BRF113771, Part A) of the effect of repeat dose dabrafenib on single dose warfarin, a CYP2C9 substrate, is ongoing. This study will provide a more definitive assessment of the inhibitory or induction risk of dabrafenib on a CYP2C9 substrate (warfarin). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=26 Page: -
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=26 Page: -	yes [IC50 8.2 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -	yes [IC50 87 uM]	unlikely Comment: [I]/Ki=0.07 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=25 Page: -	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -	yes	yes (co-administration study) Comment: A decrease in single dose midazolam CIliax and AUQo-oo) was observed with repeat dosing of dabrafenib 150 mg BID. with a mean ratio (90% CI) of 0.39 (0.24, 0.63) for Cm, and 0.26 (0.21, 0.32) for AUC(o-oo), indicating that dabrafenib induces CYP3A4-mediated metabolism (Table 12). Based on this result, dabrafenib appears to be a moderate inducer of CYP3A4 in vivo.. The effect of dabrafenib on dexamethasone, a CYP3A4 substrate, was planned as part of Study BRF113929, but subjects for that cohort could not be recruited. PK data in the only 2 subjects enrolled showed a decrease in dexamethasone concentrations with dabrafenib, consistent with CYP3A4 induction. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -	major	unknown (co-administration study) Comment: The effects of strong inhibitors or inducers of CYP3A4 or CYP2C8 on pharmacokinetics of dabrafenib in vivo are to be studied under PMRs. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -	major	yes (co-administration study) Comment: A decrease in single-dose midazolam exposure with mean (90% CI) ratios of 0.39 (0.25, 0.63) for Cmax and 0.26 (0.21, 0.32) for AUC, respectively, was observed with repeat dosing of dabrafenib 150 mg BID, indicating that dabrafenib induces CYP3A4-mediated metabolism. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=10 Page: -
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=25 Page: -	minor
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=25 Page: -	minor
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -	yes	unlikely Comment: Given the high oral bioavailability (94.5%) and high metabolic clearance, these efflux transporters appear to have minimal impact on bioavailability and contribution to the parent drug elimination. The potential impact of Pgp and/or BCRP inhibitors on the elimination of dabrafenib is considered low. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000ClinPharmR.pdf#page=27 Page: -

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/202806Orig1s000PharmR.pdf#page=5 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:75045	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75045
ChemicalBook	CB32604230	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32604230
MolPort	MolPort-028-720-422	https://www.molport.com/shop/molecule-link/MolPort-028-720-422
Selleck Chemicals	dabrafenib-gsk2118436a	http://www.selleckchem.com/products/dabrafenib-gsk2118436a.html
ZINC	ZINC000068153186	http://zinc15.docking.org/substances/ZINC000068153186
eMolecules	36008941	https://www.emolecules.com/cgi-bin/more?vid=36008941

PubMed

Title	Date	PubMed
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.	2010 Sep 30	20823850
Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies.	2013 Jul	23621583
BRAF inhibitor activity in V600R metastatic melanoma.	2013 Mar	23237741

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage regimens are: 150 mg orally taken twice daily, approximately 12 hours apart, as a single agent or 150 mg orally taken twice daily, approximately 12 hours apart, in combination with trametinib 2 mg orally taken once daily.

Route of Administration: Oral

In Vitro Use Guide

A375, SK-MEL-28, WM239 and SK-MEL-5 cells with 2.5, 5 and 10 nM dabrafenib for 72 hours. Dabrafenib treatment induced massive Mcl-1 expression at all the three concentrations. The IC50 of dabrafenib in A375, SK-MEL-28 and WM-239 was 5nM, 2nM and 6nM respectively. In dabrafenib resistant A375, SK-MEL-28 and WM-239 cells, which were denoted as A375-DR, SK-MEL-28-DR and WM-239-DR that were incubated with up to 300 nM inhibitor concentrations the IC50s were greater than 100 nM indicating more than 30-fold resistance.

Name

Type

Language

DABRAFENIB MESYLATE

Official Name

English

GSK-2118436B

Code

English

DABRAFENIB MESYLATE [USAN]

Common Name

English

DABRAFENIB MESYLATE [MI]

Common Name

English

DABRAFENIB MESYLATE [ORANGE BOOK]

Common Name

English

GSK-2118436B METHANESULFONATE SALT

Code

English

GSK-2118436B MESYLATE

Code

English

DABRAFENIB MESILATE

Common Name

English

GSK2118436B, METHANE SULFONATE SALT

Code

English

GSK2118436B

Code

English

TAFINLAR

Brand Name

English

BENZENESULFONAMIDE, N-(3-(5-(2-AMINO-4-PYRIMIDINYL)-2-(1,1-DIMETHYLETHYL)-4-THIAZOLYL)- 2-FLUOROPHENYL)-2,6-DIFLUORO-, METHANESULFONATE (1:1)

Systematic Name

English

Dabrafenib mesilate [WHO-DD]

Common Name

English

DABRAFENIB MESILATE [JAN]

Common Name

English

N-(3-(5-(2-AMINOPYRIMIDIN-4-YL)-2-(1,1-DIMETHYLETHYL)THIAZOL-4-YL)-2-FLUOROPHENYL)-2,6- DIFLUOROBENZENESULFONAMIDE MONOMETHANESULFONATE

Systematic Name

English

GSK-2118436 METHANESULFONATE SALT

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C129825