Dabrafenib

Identification

Summary

Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.

Brand Names

Tafinlar

Generic Name

Dabrafenib

DrugBank Accession Number

DB08912

Background

Dabrafenib mesylate (Tafinlar) is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway. It was approved on May 29, 2013 for the treatment of melanoma ⁷.

In May 2018, Tafinlar (dabrafenib) and Mekinist (Trametinib) in combination have been approved to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene ⁵.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 519.562
Monoisotopic: 519.101050904
Chemical Formula: C₂₃H₂₀F₃N₅O₂S₂

Synonyms

Dabrafenib

External IDs

GSK-2118436
GSK-2118436A
GSK2118436
GSK2118436A

Pharmacology

Indication

Tafinlar is a kinase inhibitor that was initially 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 ^Label.

Tafinlar in combination with Trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for Tafinlar in combination with trametinib ^Label.

In May 2018, Tafinlar (dabrafenib) and Mekinist (Trametinib) have been approved in combination to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene ³.

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Associated Conditions

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Pharmacodynamics

Dabrafenib causes an inhibition of phosphorylated extracellular signal-regulated kinase (ERK). This indicates a decrease in cell proliferation. Furthermore, within 24 hours of administration, downstream mediators of the MAPK pathway were inhibited ^Label.

The melanoma approval for use with Mekinist is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection. Patients received doses of Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met ⁵. Thus, Tafinlar in combination with Mekinist treats melanoma.

In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease ⁸.

Mechanism of action

Dabrafenib is an orally bioavailable inhibitor of B-raf (BRAF) protein with antineoplastic activity. Dabrafenib selectively binds to and inhibits the activity of B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. B-raf belongs to the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/Extracellular Signal-regulated Kinases signaling pathway, which may be constitutively activated due to BRAF gene mutations ^Label.

Target	Actions	Organism
ASerine/threonine-protein kinase B-raf	antagonist inhibitor	Humans
ARAF proto-oncogene serine/threonine-protein kinase	antagonist inhibitor	Humans
USerine/threonine-protein kinase SIK1	antagonist inhibitor	Humans
USerine/threonine-protein kinase Nek11	antagonist inhibitor	Humans
ULIM domain kinase 1	antagonist inhibitor	Humans

Absorption

After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95% ².

Volume of distribution

Apparent volume of distribution (Vd/F) = 70.3 L ^Label. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein ^Label.

Protein binding

99.7% bound to human plasma protein ^Label.

Metabolism

Dabrafenib is metabolized in the liver. The biotransformation process of this drug is primarily regulated by CYP2C8 and CYP3A4 to form hydroxy-debrafenib. This metabolite is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib can also undergo decarboxylation to form desmethyl-dabrafenib, which may be reabsorbed from the gastrointestinal tract. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites ², ^Label.

Route of elimination

Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only ^Label.

Half-life

The average terminal half-life of dabrafenib is 8 hours after oral dosing ^Label.

Clearance

The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice daily dosing ^Label

Adverse Effects

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Toxicity

LD50 in rats is > 2000 mg/kg ^MSDS.

The most common side effects of Daretinib (Tafinlar) as a single agent include: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome ^Label.

The most common adverse reactions (≥20%) for Tafinlar in combination with Trametinib are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia ^Label.

The following is a list of toxicities that may occur with the combination of Daretinib and Trametinib:

New primary malignancies: These may occur when Tafinlar is administered as a single agent or in combination with Trametinib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of TAFINLAR or the combination therapy. Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors ^Label.

Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding ^Label.

Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving the drug combination ^Label.

*Cardiomyopathy *: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter ^Label.

Ocular toxicities: Perform an ophthalmologic evaluation for any visual disturbances ^Label.

Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib ^Label.

Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite the interruption of TAFINLAR ^Label.

Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia ^Label.

Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia ^Label.

Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used ^Label.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Glucose-6-phosphate 1-dehydrogenase	Villeurbanne	Not Available	1000_1002delACC	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Torun	Not Available	1006A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Sunderland	Not Available	105_107delCAT	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Iwatsuki	Not Available	1081G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Serres	Not Available	1082C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Tondela	Not Available	1084_1101delCTGAACGAGCGCAAGGCC	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Loma Linda	Not Available	1089C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Aachen	Not Available	1089C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Tenri	Not Available	1096A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Montpellier	Not Available	1132G>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Calvo Mackenna	Not Available	1138A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Riley	Not Available	1139T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Olomouc	Not Available	1141T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Tomah	Not Available	1153T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Lynwood	Not Available	1154G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Madrid	Not Available	1155C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Iowa, Walter Reed, Springfield	Not Available	1156A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Beverly Hills, Genova, Iwate, Niigata, Yamaguchi	Not Available	1160G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Hartford	Not Available	1162A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Praha	Not Available	1166A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Krakow	Not Available	1175T>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Wisconsin	Not Available	1177C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Nashville, Anaheim, Portici	Not Available	1178G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Alhambra	Not Available	1180G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Bari	Not Available	1187C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Puerto Limon	Not Available	1192G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Covao do Lobo	Not Available	1205C>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Clinic	Not Available	1215G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Utrecht	Not Available	1225C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Suwalki	Not Available	1226C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Riverside	Not Available	1228G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Japan, Shinagawa	Not Available	1229G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kawasaki	Not Available	1229G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Munich	Not Available	1231A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Georgia	Not Available	1284C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Sumare	Not Available	1292T->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Telti/Kobe	Not Available	1318C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Santiago de Cuba, Morioka	Not Available	1339G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Harima	Not Available	1358T->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Figuera da Foz	Not Available	1366G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Amiens	Not Available	1367A>T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Bangkok Noi	Not Available	1376G->T, 1502T->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Fukaya	Not Available	1462G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Campinas	Not Available	1463G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Buenos Aires	Not Available	1465C>T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Arakawa	Not Available	1466C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Brighton	Not Available	1488_1490delGAA	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kozukata	Not Available	159G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Amsterdam	Not Available	180_182delTCT	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	No name	Not Available	202G->A, 376A->G, 1264C>G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Swansea	Not Available	224T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Urayasu	Not Available	281_283delAGA	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Vancouver	Not Available	317C->G544C->T592C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Mt Sinai	Not Available	376A->G, 1159C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Plymouth	Not Available	488G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Volendam	Not Available	514C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Shinshu	Not Available	527A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Chikugo	Not Available	535A->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Tsukui	Not Available	561_563delCTC	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Pedoplis-Ckaro	Not Available	573C>G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Santiago	Not Available	593G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Minnesota, Marion, Gastonia, LeJeune	Not Available	637G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Cincinnati	Not Available	637G->T, 1037A->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Harilaou	Not Available	648T->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	North Dallas	Not Available	683_685delACA	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Asahikawa	Not Available	695G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Durham	Not Available	713A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Stonybrook	Not Available	724_729delGGCACT	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Wayne	Not Available	769C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Aveiro	Not Available	806G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Cleveland Corum	Not Available	820G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Lille	Not Available	821A>T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Bangkok	Not Available	825G>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Sugao	Not Available	826C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	La Jolla	Not Available	832T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Wexham	Not Available	833C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Piotrkow	Not Available	851T>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	West Virginia	Not Available	910G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Omiya	Not Available	921G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Nara	Not Available	953_976delCCACCAAAGGGTACCTGGAC GACC	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Manhattan	Not Available	962G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Rehevot	Not Available	964T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Honiara	Not Available	99A->G / 1360C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Tokyo, Fukushima	Not Available	1246G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Chatham	Not Available	1003G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Fushan	Not Available	1004C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Partenope	Not Available	1052G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Ierapetra	Not Available	1057C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Anadia	Not Available	1193A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Abeno	Not Available	1220A->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Surabaya	Not Available	1291G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Pawnee	Not Available	1316G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	S. Antioco	Not Available	1342A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Cassano	Not Available	1347G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Hermoupolis	Not Available	1347G->C / 1360C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Union,Maewo, Chinese-2, Kalo	Not Available	1360C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Andalus	Not Available	1361G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Cosenza	Not Available	1376G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Canton, Taiwan- Hakka, Gifu-like, Agrigento-like	Not Available	1376G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Flores	Not Available	1387C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kaiping, Anant, Dhon, Sapporo-like, Wosera	Not Available	1388G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kamogawa	Not Available	169C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Costanzo	Not Available	179T>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Amazonia	Not Available	185C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Songklanagarind	Not Available	196T->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Hechi	Not Available	202G->A / 871G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Namouru	Not Available	208T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Bao Loc	Not Available	352T>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Crispim	Not Available	375G->T, 379G->T383T->C384C>T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Acrokorinthos	Not Available	376A->G / 463C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Santa Maria	Not Available	376A->G / 542A->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Ananindeua	Not Available	376A->G / 871G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Vanua Lava	Not Available	383T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Valladolid	Not Available	406C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Belem	Not Available	409C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Liuzhou	Not Available	442G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Shenzen	Not Available	473G>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Taipei ‚ÄúChinese- 3‚Äù	Not Available	493A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Toledo	Not Available	496C>T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Naone	Not Available	497G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Nankang	Not Available	517T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Miaoli	Not Available	519C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Mediterranean, Dallas, Panama‚ Sassari, Cagliari, Birmingham	Not Available	563C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Coimbra Shunde	Not Available	592C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Nilgiri	Not Available	593G>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Radlowo	Not Available	679C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Roubaix	Not Available	811G>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Haikou	Not Available	835A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Chinese-1	Not Available	835A->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Mizushima	Not Available	848A>G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Osaka	Not Available	853C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Viangchan, Jammu	Not Available	871G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Seoul	Not Available	916G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Ludhiana	Not Available	929G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Farroupilha	Not Available	977C->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Chinese-5	Not Available	1024C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Rignano	Not Available	130G>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Orissa	Not Available	131C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	G6PDNice	Not Available	1380G>C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kamiube, Keelung	Not Available	1387C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Neapolis	Not Available	1400C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Aures	Not Available	143T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Split	Not Available	1442C->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kambos	Not Available	148C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Palestrina	Not Available	170G>A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Metaponto	Not Available	172G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Musashino	Not Available	185C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Asahi	Not Available	202G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	A- (202), Ferrara I	Not Available	202G->A / 376A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Murcia Oristano	Not Available	209A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Ube Konan	Not Available	241C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Lagosanto	Not Available	242G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Guangzhou	Not Available	274C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Hammersmith	Not Available	323T->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Sinnai	Not Available	34G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	A- (680)	Not Available	376A->G / 680G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	A- (968), Betica,Selma, Guantanamo	Not Available	376A->G / 968T->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Salerno Pyrgos	Not Available	383T>G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Quing Yan	Not Available	392G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Lages	Not Available	40G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Ilesha	Not Available	466G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Mahidol	Not Available	487G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Malaga	Not Available	542A->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Sibari	Not Available	634A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Mexico City	Not Available	680G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Nanning	Not Available	703C->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Seattle, Lodi, Modena, Ferrara II, Athens-like	Not Available	844G->C	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Bajo Maumere	Not Available	844G->T	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Montalbano	Not Available	854G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Kalyan-Kerala, Jamnaga, Rohini	Not Available	949G->A	ADR Inferred	Increased risk of hemolytic anemia.	Details
Glucose-6-phosphate 1-dehydrogenase	Gaohe	Not Available	95A->G	ADR Inferred	Increased risk of hemolytic anemia.	Details

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abametapir	The serum concentration of Dabrafenib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Dabrafenib can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Dabrafenib.
Abiraterone	The metabolism of Dabrafenib can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Dabrafenib.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Dabrafenib.
Acarbose	The therapeutic efficacy of Acarbose can be decreased when used in combination with Dabrafenib.
Acenocoumarol	The serum concentration of Acenocoumarol can be decreased when it is combined with Dabrafenib.
Acetaminophen	The metabolism of Dabrafenib can be increased when combined with Acetaminophen.
Acetazolamide	The metabolism of Dabrafenib can be decreased when combined with Acetazolamide.

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Food Interactions

Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of dabrafenib.
Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dabrafenib.
Do not take with or immediately after a high-fat meal. Dabrafenib's bioavailability is reduced when taken with a high-fat meal.
Take on an empty stomach. Take dabrafenib at least one hour before or two hours after a meal.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Dabrafenib mesylate	B6DC89I63E	1195768-06-9	YKGMKSIHIVVYKY-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Tafinlar	Capsule	50 mg/1	Oral	Glaxosmithkline Inc	2013-06-10	2018-08-31
Tafinlar	Capsule	75 mg	Oral	Novartis	2013-08-28	Not applicable
Tafinlar	Capsule	75 mg	Oral	Novartis Europharm Limited	2021-03-17	Not applicable
Tafinlar	Capsule	75 mg/1	Oral	Novartis Pharmaceuticals Corporation	2016-04-01	Not applicable
Tafinlar	Capsule	50 mg/1	Oral	Glaxosmithkline Inc	2013-06-10	Not applicable
Tafinlar	Capsule	50 mg	Oral	Novartis	2013-08-28	Not applicable
Tafinlar	Capsule	50 mg	Oral	Novartis Europharm Limited	2021-03-17	Not applicable
Tafinlar	Capsule	50 mg/1	Oral	Novartis Pharmaceuticals Corporation	2016-04-12	Not applicable
Tafinlar	Capsule	75 mg/1	Oral	Glaxosmithkline Inc	2013-06-10	2018-05-31
Tafinlar	Capsule	75 mg	Oral	Novartis Europharm Limited	2021-03-17	Not applicable

Chemical Identifiers

UNII: QGP4HA4G1B
CAS number: 1195765-45-7
InChI Key: BFSMGDJOXZAERB-UHFFFAOYSA-N
InChI: InChI=1S/C23H20F3N5O2S2/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/h4-11,31H,1-3H3,(H2,27,28,29)
IUPAC Name: N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene-1-sulfonamide
SMILES: CC(C)(C)C1=NC(=C(S1)C1=NC(N)=NC=C1)C1=C(F)C(NS(=O)(=O)C2=C(F)C=CC=C2F)=CC=C1

References

General References

Gibney GT, Zager JS: Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9. doi: 10.1517/17425255.2013.794220. Epub 2013 Apr 29. [Article]
Dabrafenib [Link]
Drug Duo, Tafinlar and Mekinist, Approved for Aggressive Thyroid Cancer [Link]
FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation [Link]
Novartis receives FDA approval of Tafinlar® + Mekinist® for adjuvant treatment of BRAF V600-mutant melanoma [Link]
Dabrafenib [Link]
Cancer. gov Dabrafenib [Link]
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer [Link]
NZ DrugSafe Tafinlar [File]
Monograph, Tafinlar [File]

External Links

KEGG Drug: D10064
PubChem Compound: 44462760
PubChem Substance: 175427150
ChemSpider: 25948204
BindingDB: 50428286
RxNav: 1424911
ChEBI: 75045
ChEMBL: CHEMBL2028663
ZINC: ZINC000068153186
PDBe Ligand: P06
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Dabrafenib

AHFS Codes

10:00.00 — Antineoplastic Agents

PDB Entries

4xv2 / 5csw / 5hie / 6hj2 / 6v2u

FDA label

Download (418 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Anaplastic Astrocytoma (AA) / Anaplastic Ganglioglioma / Anaplastic Oligodendroglioma (AO) / Anaplastic Pleomorphic Xanthoastrocytoma / Angiocentric glioma / Astrocytomas / Central Neurocytoma / Cerebellar Liponeurocytoma / Chordoid Glioma of Third Ventricle / Desmoplastic Infantile Astrocytoma and Ganglioglioma / Diffuse Astrocytoma / Dysplastic Gangliocytoma of Cerebrellum / Extraventricular Neurocytoma / Gangliocytoma / Ganglioglioma / Giant Cell Astrocytoma / Glioblastomas / Neurofibromatosis Type 1 / Oligodendroglioma, Childhood / Papillary Glioneuronal Tumor / Pilocytic Astrocytoma / Pleomorphic Xanthoastrocytoma / Rosette-forming Glioneurona Tumor	1
4	Recruiting	Treatment	High Grade Glioma (HGG) / Melanomas / Non-Small Cell Lung Carcinoma (NSCLC) / Rare Cancers / Tumors, Solid	1
3	Active Not Recruiting	Treatment	Melanoma, Malignant	1
3	Active Not Recruiting	Treatment	Melanomas	2
3	Completed	Treatment	Malignancies	1
3	Completed	Treatment	Melanomas	2
3	Recruiting	Health Services Research	Soft Tissue Sarcoma (STS)	1
3	Recruiting	Treatment	Metastatic Melanoma / Recurrent Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Unresectable Cutaneous Melanoma	1
2	Active Not Recruiting	Treatment	Advanced Lymphoma / Advanced Malignant Solid Neoplasm / Hematopoietic and Lymphoid Cell Neoplasm / Refractory Lymphomas / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma	1
2	Active Not Recruiting	Treatment	Anaplastic Astrocytoma (AA) / Anaplastic Ganglioglioma / Anaplastic Oligodendroglioma (AO) / Anaplastic Pleomorphic Xanthoastrocytoma / Angiocentric glioma / Astrocytomas / Central Neurocytoma / Cerebellar Iponeurocytoma / Chordoid Glioma of Third Ventricle / Desmoplastic Infantile Astrocytoma and Ganglioglioma / Diffuse Astrocytoma / Dysplastic Gangliocytoma of Cerebrellum / Extraventricular Neurocytoma / Gangliocytoma / Ganglioglioma / Giant Cell Astrocytoma / Glioblastomas / Oligodendroglioma, Childhood / Papillary Glioneuronal Tumor / Pilocytic Astrocytoma / Pleomorphic Xanthoastrocytoma / Rosette-forming Glioneurona Tumor	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule	Oral	50 mg/1
Capsule	Oral	75 mg/1
Capsule	Oral	50 mg
Capsule	Oral	75 mg
Capsule, coated	Oral	50 mg
Capsule, coated	Oral	75 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US7994185	No	2011-08-09	2030-01-20
US8415345	No	2013-04-09	2030-01-20
US9233956	No	2016-01-12	2029-05-04
US8703781	No	2014-04-22	2030-10-15
US8835443	No	2014-09-16	2025-09-13
US8952018	No	2015-02-10	2030-10-15

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	very slightly soluble at pH 1	http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf
logP	2.9	http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf
pKa	-1.5	http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.00327 mg/mL	ALOGPS
logP	5.44	ALOGPS
logP	5.46	ChemAxon
logS	-5.2	ALOGPS
pKa (Strongest Acidic)	7.16	ChemAxon
pKa (Strongest Basic)	2.91	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	110.86 Å²	ChemAxon
Rotatable Bond Count	5	ChemAxon
Refractivity	127.51 m³·mol^-1	ChemAxon
Polarizability	49.71 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9944
Blood Brain Barrier	+	0.7232
Caco-2 permeable	+	0.5069
P-glycoprotein substrate	Non-substrate	0.7965
P-glycoprotein inhibitor I	Non-inhibitor	0.6468
P-glycoprotein inhibitor II	Non-inhibitor	0.7039
Renal organic cation transporter	Non-inhibitor	0.8694
CYP450 2C9 substrate	Non-substrate	0.8233
CYP450 2D6 substrate	Non-substrate	0.7346
CYP450 3A4 substrate	Non-substrate	0.5834
CYP450 1A2 substrate	Inhibitor	0.5219
CYP450 2C9 inhibitor	Inhibitor	0.5
CYP450 2D6 inhibitor	Non-inhibitor	0.8459
CYP450 2C19 inhibitor	Non-inhibitor	0.5
CYP450 3A4 inhibitor	Inhibitor	0.7531
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.8612
Ames test	Non AMES toxic	0.7078
Carcinogenicity	Non-carcinogens	0.8093
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.4329 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9848
hERG inhibition (predictor II)	Non-inhibitor	0.7704

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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with our fully connected ADMET & drug target dataset.

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Accelerate your drug discovery research with our ADMET & drug target dataset

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Details1. Serine/threonine-protein kinase B-raf

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Protein serine/threonine kinase activity
Specific Function: Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, a...
Gene Name: BRAF
Uniprot ID: P15056
Uniprot Name: Serine/threonine-protein kinase B-raf
Molecular Weight: 84436.135 Da

References

Gibney GT, Zager JS: Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9. doi: 10.1517/17425255.2013.794220. Epub 2013 Apr 29. [Article]
Dabrafenib [Link]

Details2. RAF proto-oncogene serine/threonine-protein kinase

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Protein serine/threonine kinase activity
Specific Function: Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determin...
Gene Name: RAF1
Uniprot ID: P04049
Uniprot Name: RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight: 73051.025 Da

References

Dabrafenib [Link]
Monograph, Tafinlar [File]

Details3. Serine/threonine-protein kinase SIK1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Antagonist
Inhibitor

General Function: Protein serine/threonine kinase activity
Specific Function: Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Pho...
Gene Name: SIK1
Uniprot ID: P57059
Uniprot Name: Serine/threonine-protein kinase SIK1
Molecular Weight: 84901.25 Da

References

Dabrafenib [Link]
Monograph, Tafinlar [File]

Details4. Serine/threonine-protein kinase Nek11

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Antagonist
Inhibitor

General Function: Protein serine/threonine kinase activity
Specific Function: Protein kinase which plays an important role in the G2/M checkpoint response to DNA damage. Controls degradation of CDC25A by directly phosphorylating it on residues whose phosphorylation is requir...
Gene Name: NEK11
Uniprot ID: Q8NG66
Uniprot Name: Serine/threonine-protein kinase Nek11
Molecular Weight: 74191.62 Da

References

Dabrafenib [Link]
Monograph, Tafinlar [File]

Details5. LIM domain kinase 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Antagonist
Inhibitor

General Function: Zinc ion binding
Specific Function: Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by up...
Gene Name: LIMK1
Uniprot ID: P53667
Uniprot Name: LIM domain kinase 1
Molecular Weight: 72584.4 Da

References

Dabrafenib [Link]
Monograph, Tafinlar [File]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor
Inducer

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Rowland A, van Dyk M, Hopkins AM, Mounzer R, Polasek TM, Rostami-Hodjegan A, Sorich MJ: Physiologically Based Pharmacokinetic Modeling to Identify Physiological and Molecular Characteristics Driving Variability in Drug Exposure. Clin Pharmacol Ther. 2018 Dec;104(6):1219-1228. doi: 10.1002/cpt.1076. Epub 2018 Apr 19. [Article]
Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]
Dabrafenib FDA label [Link]

Details2. Cytochrome P450 2C8

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor
Inducer

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2C8
Uniprot ID: P10632
Uniprot Name: Cytochrome P450 2C8
Molecular Weight: 55824.275 Da

References

Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [Article]
Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]

Details3. Cytochrome P450 2B6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2B6
Uniprot ID: P20813
Uniprot Name: Cytochrome P450 2B6
Molecular Weight: 56277.81 Da

References

Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]

Details4. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inducer

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2C9
Uniprot ID: P11712
Uniprot Name: Cytochrome P450 2C9
Molecular Weight: 55627.365 Da

References

Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, LoRusso PM, Infante JR, Sharma S, Kendra K, Patel M, Pant S, Arkenau HT, Middleton MR, Blackman SC, Botbyl J, Carson SW: Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015 Apr;55(4):392-400. doi: 10.1002/jcph.437. Epub 2014 Dec 30. [Article]
Brody T. (2018). FDA's Drugreview Process and the Package Label. Academic Press.
EMA Label: Tafinlar (dabrafenib mesilate) Summary of Product Characteristics [File]

Details5. Cytochrome P450 2C19

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Inducer

General Function: Steroid hydroxylase activity
Specific Function: Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name: CYP2C19
Uniprot ID: P33261
Uniprot Name: Cytochrome P450 2C19
Molecular Weight: 55930.545 Da

References

Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]
EMA Label: Tafinlar (dabrafenib mesilate) Summary of Product Characteristics [File]

Details6. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP1A2
Uniprot ID: P05177
Uniprot Name: Cytochrome P450 1A2
Molecular Weight: 58293.76 Da

References

Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]

Transporters

Details1. P-glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17. [Article]

Details2. ATP-binding cassette sub-family G member 2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Xenobiotic-transporting atpase activity
Specific Function: High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: ATP-binding cassette sub-family G member 2
Molecular Weight: 72313.47 Da

References

Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17. [Article]

Details3. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

Details4. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

Details5. Solute carrier family 22 member 6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name: SLC22A6
Uniprot ID: Q4U2R8
Uniprot Name: Solute carrier family 22 member 6
Molecular Weight: 61815.78 Da

Details6. Solute carrier family 22 member 8

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name: SLC22A8
Uniprot ID: Q8TCC7
Uniprot Name: Solute carrier family 22 member 8
Molecular Weight: 59855.585 Da

Drug created on June 24, 2013 21:54 / Updated on June 17, 2021 15:27

Dabrafenib

Identification

Structure for Dabrafenib (DB08912)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

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Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

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Enzymes

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Transporters

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