Identification

Name

Binimetinib

Accession Number

DB11967

Description

Binimetinib, also known as Mektovi, is a potent is a potent and selective oral mitogen-activated protein kinase 1/2 (MEK 1/2) inhibitor which is combined with Encorafenib ⁴,⁸.

On June 27, 2018, the Food and Drug Administration approved the combination of Encorafenib and binimetinib (BRAFTOVI and MEKTOVI, from Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutations, as detected by an FDA-approved test ⁸.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Binimetinib (DB11967)

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Weight

Average: 441.233
Monoisotopic: 440.02956

Chemical Formula

C₁₇H₁₅BrF₂N₄O₃

Synonyms

• Binimetinib

External IDs

• ARRY-162
• ARRY-438162
• MEK-162
• MEK162
• NVP-MEK162

Pharmacology

Indication

On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib in combination patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test ⁸.

Associated Conditions

• Metastatic Melanoma
• Unresectable Melanoma

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

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Pharmacodynamics

Binimetinib is a MEK inhibitor. MEK is an enzyme that regulates the biosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. MEK inhibitors interfere with these biosynthetic processes ⁷. It is a chemotherapeutic agent that has anti-tumor activity ¹⁰, ¹.

Mechanism of action

Binimetinib, noncompetitive with ATP, binds to and inhibits the activity of MEK1/2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors. This process can result in the inhibition of growth factor-mediated cell signaling. This may lead to the inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor. MEK1/2 are themselves threonine and tyrosine kinases that possess a dual specificity. They subsequently contribute critically to the activation of the RAS/RAF/MEK/ERK pathway and are typically upregulated in a number of different tumor cell types ⁷.

Target	Actions	Organism
UInterleukin-6	Not Available	Humans
UTumor necrosis factor	Not Available	Humans
UInterleukin-1 beta	Not Available	Humans
AMitogen-activated protein kinase kinase kinase 1	inhibitor	Humans
ADual specificity mitogen-activated protein kinase kinase 2	inhibitor	Humans

Absorption

Following oral administration in a pharmacokinetic study, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours ^Label.

The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure ^Label.

Volume of distribution

The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%) ^Label

Protein binding

Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72 ^Label

Metabolism

The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib ^Label.

Route of elimination

Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine ^Label.

Half-life

The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) ^Label.

Clearance

20.2 L/h (24%) ^Label

Adverse Effects

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Toxicity

The most common (≥25%) adverse reactions in patients receiving the combination of this drug with Encorafenib were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. Discontinuation of therapy due to adverse reactions occurred in 5% of patients receiving the combination; the most common reasons were hemorrhage and headache ⁸.

Due to the variety of adverse events associated with this drug, adverse events are categorized by system ¹²:

Systemic events: Fatigue (31%) ¹²

Musculoskeletal system: Rhabdomyolysis ¹²

Ophthalmic events: Retinal hemorrhage, retinal detachment (6%), macular edema, serous retinopathy (20%) ¹²

Circulatory system: Hypertension, thromboembolic events such as DVT, resulting in pulmonary embolism (5.6%), peripheral edema or periorbital edema (43.5%), hemorrhage (11.2%)¹²

Pulmonary events: Pneumonitis (1.9%), Pulmonary embolism ¹²

Cardiovascular system: QT interval prolongation (3.3%), Left ventricular dysfunction (7%) ¹²

Gastrointestinal system: Hepatotoxicity, diarrhea, nausea, vomiting, stomatitis, dry mouth ¹²

Dermatologic events: Acneiform dermatitis ⁹

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman ^Label.

Affected organisms

• Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Binimetinib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Binimetinib can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Binimetinib can be increased when it is combined with Abiraterone.
Acenocoumarol	The metabolism of Binimetinib can be decreased when combined with Acenocoumarol.
Acetaminophen	The metabolism of Binimetinib can be decreased when combined with Acetaminophen.
Acyclovir	The metabolism of Binimetinib can be decreased when combined with Acyclovir.
Adalimumab	The metabolism of Binimetinib can be increased when combined with Adalimumab.
Adenine	The metabolism of Binimetinib can be decreased when combined with Adenine.
Afatinib	The serum concentration of Binimetinib can be increased when it is combined with Afatinib.
Agomelatine	The metabolism of Binimetinib can be decreased when combined with Agomelatine.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Take with or without food.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
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Mektovi	Tablet, film coated	15 mg/1	Oral	Array BioPharma Inc.	2018-06-27	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L01XE41 — Binimetinib

• L01XE — Protein kinase inhibitors
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 Substrates
• Heterocyclic Compounds, Fused-Ring
• MAP Kinase Kinase 1, antagonists & inhibitors
• MAP Kinase Kinase 2, antagonists & inhibitors
• P-glycoprotein substrates with narrow therapeutic index
• Protein Kinase Inhibitors
• UGT1A1 Substrates
• UGT1A1 substrates with narrow therapeutic index

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 3-halobenzoic acids and derivatives. These are benzoic acids or derivatives carrying a halogen atom at the 3-position of the benzene ring.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzoic acids and derivatives

Direct Parent

3-halobenzoic acids and derivatives

Alternative Parents

Benzimidazoles / Aniline and substituted anilines / Fluorobenzenes / Bromobenzenes / Primary aromatic amines / Aryl bromides / Aryl fluorides / N-substituted imidazoles / Vinylogous amides / Heteroaromatic compounds / Amino acids and derivatives / Secondary amines / Azacyclic compounds / Hydrocarbon derivatives / Organic oxides / Organobromides / Organofluorides / Primary alcohols

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Substituents

3-halobenzoic acid or derivatives / Alcohol / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl bromide / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzimidazole / Bromobenzene / Carboxylic acid derivative / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / N-substituted imidazole / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organobromide / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Primary alcohol / Primary aromatic amine / Secondary amine / Vinylogous amide

show 23 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

181R97MR71

CAS number

606143-89-9

InChI Key

ACWZRVQXLIRSDF-UHFFFAOYSA-N

InChI

InChI=1S/C17H15BrF2N4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)

IUPAC Name

5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-1,3-benzodiazole-6-carboxamide

SMILES

CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3F)=C(C=C12)C(=O)NOCCO

References

General References

1. Koelblinger P, Dornbierer J, Dummer R: A review of binimetinib for the treatment of mutant cutaneous melanoma. Future Oncol. 2017 Aug;13(20):1755-1766. doi: 10.2217/fon-2017-0170. Epub 2017 Jun 7. [PubMed:28587477]
2. Queirolo P, Spagnolo F: Binimetinib for the treatment of NRAS-mutant melanoma. Expert Rev Anticancer Ther. 2017 Nov;17(11):985-990. doi: 10.1080/14737140.2017.1374177. Epub 2017 Sep 8. [PubMed:28851243]
3. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozon V, Long GV, Flaherty K: Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8. Epub 2017 Mar 9. [PubMed:28284557]
4. Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, Weekes CD, Tan BR, Khan GN, Zalupski MM, Infante JR, Jones S, Papadopoulos KP, Tolcher AW, Chavira RE, Christy-Bittel JL, Barrett E, Patnaik A: A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017 Feb 28;116(5):575-583. doi: 10.1038/bjc.2017.10. Epub 2017 Feb 2. [PubMed:28152546]
5. Gardner AM, Vaillancourt RR, Lange-Carter CA, Johnson GL: MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity. Mol Biol Cell. 1994 Feb;5(2):193-201. [PubMed:8019005]
6. Wang ZQ, Wu DC, Huang FP, Yang GY: Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res. 2004 Jan 16;996(1):55-66. [PubMed:14670631]
7. Cancer.gov link [Link]
8. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
9. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor [Link]
10. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression [Link]
11. Binimetinib [File]
12. EMA assessment [File]

External Links

PubChem Compound

10288191

PubChem Substance

347828291

ChemSpider

8463660

ChEBI

145371

ChEMBL

CHEMBL3187723

ZINC

ZINC000038460704

PharmGKB

PA166179867

Wikipedia

Binimetinib

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	BRAF V600E-mutant Metastatic Colorectal Cancer	1
3	Active Not Recruiting	Treatment	Low-grade Serous Fallopian Tube Cancer / Low-grade Serous Ovarian Cancer / Low-grade Serous Peritoneal Cancer	1
3	Active Not Recruiting	Treatment	Melanoma	1
3	Completed	Treatment	Metastatic or Unresectable Cutaneous Melanoma	1
3	Recruiting	Treatment	Metastatic Colorectal Cancer (MCRC) / Stage III Colorectal Cancer	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	BRAF or NRAS Mutant Metastatic Melanoma	1
2	Active Not Recruiting	Treatment	BRAF V600E-mutant Metastatic Colorectal Cancer	1
2	Active Not Recruiting	Treatment	Melanoma	1
2	Active Not Recruiting	Treatment	Metastatic Melanoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	15 mg/1
Tablet, film coated	Oral	15 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US9314464	No	2016-04-19	2031-07-04
US9850229	No	2017-12-26	2030-08-27
US10005761	No	2018-06-26	2030-08-27
US9593100	No	2017-03-14	2030-08-27
US9980944	No	2018-05-29	2033-10-18
US9598376	No	2017-03-21	2033-10-18
US8193229	No	2012-06-05	2023-03-13
US8513293	No	2013-08-20	2023-03-13
US7777050	No	2010-08-17	2023-03-13
US8178693	No	2012-05-15	2023-03-13
US9562016	No	2017-02-07	2033-10-18

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0499 mg/mL	ALOGPS
logP	3	ALOGPS
logP	3.81	ChemAxon
logS	-4	ALOGPS
pKa (Strongest Acidic)	10.26	ChemAxon
pKa (Strongest Basic)	5.3	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	88.41 Å2	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	98.02 m3·mol-1	ChemAxon
Polarizability	38.55 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

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

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Drug created on October 20, 2016 15:06 / Updated on June 12, 2020 11:42