Identification
- Summary
Binimetinib is a medication used to treat metastatic melanoma with specific mutations.
- Brand Names
- Mektovi
- Generic Name
- Binimetinib
- DrugBank Accession Number
- DB11967
- Background
Binimetinib, also known as Mektovi, 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
Structure for Binimetinib (DB11967)
- 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.
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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 AMitogen-activated protein kinase kinase kinase 1 inhibitorHumans ADual specificity mitogen-activated protein kinase kinase 2 inhibitorHumans UInterleukin-6 Not Available Humans UTumor necrosis factor Not Available Humans UInterleukin-1 beta Not Available 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- 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.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir 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. Abrocitinib The serum concentration of Binimetinib can be increased when it is combined with Abrocitinib. 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. 
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- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Mektovi Tablet, film coated 15 mg Oral Pierre Fabre Médicament 2020-12-16 Not applicable EU 
Mektovi Tablet, film coated 15 mg/1 Oral Array BioPharma Inc. 2018-06-27 Not applicable US 
Mektovi Tablet, film coated 15 mg Oral Pierre Fabre Médicament 2020-12-16 Not applicable EU Mektovi Tablet 15 mg Oral Pfizer Canada Ulc 2021-07-05 Not applicable Canada 
Categories
- ATC Codes
- L01EE03 — Binimetinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP1A2 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C19 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- MAP Kinase Kinase 1, antagonists & inhibitors
- MAP Kinase Kinase 2, antagonists & inhibitors
- Mitogen-activated protein kinase (MEK) inhibitors
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Protein Kinase Inhibitors
- UGT1A1 Substrates
- UGT1A1 Substrates with a 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 show 8 more
- 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 show 23 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Cancer.gov link [Link]
- FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
- A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor [Link]
- Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression [Link]
- Binimetinib [File]
- EMA assessment [File]
- External Links
- PubChem Compound
- 10288191
- PubChem Substance
- 347828291
- ChemSpider
- 8463660
- ChEBI
- 145371
- ChEMBL
- CHEMBL3187723
- ZINC
- ZINC000038460704
- PharmGKB
- PA166179867
- PDBe Ligand
- QO7
- Wikipedia
- Binimetinib
- PDB Entries
- 7m0u
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 15 mg Tablet, film coated Oral 15 MG Tablet, film coated Oral 15 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9314464 No 2016-04-19 2031-07-04 US US9850229 No 2017-12-26 2030-08-27 US US10005761 No 2018-06-26 2030-08-27 US US9593100 No 2017-03-14 2030-08-27 US US9980944 No 2018-05-29 2033-10-18 US US9598376 No 2017-03-21 2033-10-18 US US8193229 No 2012-06-05 2023-03-13 US US8513293 No 2013-08-20 2023-03-13 US US7777050 No 2010-08-17 2023-03-13 US US8178693 No 2012-05-15 2023-03-13 US US9562016 No 2017-02-07 2033-10-18 US
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
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- Component of a protein kinase signal transduction cascade. Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB, the central protein kinases o...
- Gene Name
- MAP3K1
- Uniprot ID
- Q13233
- Uniprot Name
- Mitogen-activated protein kinase kinase kinase 1
- Molecular Weight
- 164468.265 Da
References
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Scaffold protein binding
- Specific Function
- Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
- Gene Name
- MAP2K2
- Uniprot ID
- P36507
- Uniprot Name
- Dual specificity mitogen-activated protein kinase kinase 2
- Molecular Weight
- 44423.735 Da
References
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Interleukin-6 receptor binding
- Specific Function
- Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Inv...
- Gene Name
- IL6
- Uniprot ID
- P05231
- Uniprot Name
- Interleukin-6
- Molecular Weight
- 23717.965 Da
References
- Cancer.gov link [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Tumor necrosis factor receptor binding
- Specific Function
- Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
- Gene Name
- TNF
- Uniprot ID
- P01375
- Uniprot Name
- Tumor necrosis factor
- Molecular Weight
- 25644.15 Da
References
- Cancer.gov link [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Protein domain specific binding
- Specific Function
- Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, ...
- Gene Name
- IL1B
- Uniprot ID
- P01584
- Uniprot Name
- Interleukin-1 beta
- Molecular Weight
- 30747.7 Da
References
- Cancer.gov link [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid binding
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1-1
- Molecular Weight
- 59590.91 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
Drug created at October 20, 2016 21:06 / Updated at April 01, 2022 20:22