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.2,4
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.4
- 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
Binimetinib, in conjunction with encorafenib, is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.5
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- Contraindications & Blackbox Warnings
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In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.5 MEK is an enzyme that regulates the biosynthesis of inflammatory cytokines such as TNF, IL-6 and IL-1; therefore, binimetinib anti-tumor activity can be mediated through the interference of cytokines biosynthesis.1,3
Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.5
Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.5
- Mechanism of action
Binimetinib, noncompetitive with ATP, binds reversibly to and inhibits the activity of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and 2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, resulting in the inhibition of growth factor-mediated cell signaling such as the downstream extracellular signal-related kinase (ERK) pathway. 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.3,5
Target Actions Organism ADual specificity mitogen-activated protein kinase kinase 2 inhibitorHumans ADual specificity mitogen-activated protein kinase kinase 1 inhibitorHumans - Absorption
The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is <40% at steady state. The systemic exposure of binimetinib is approximately dose proportional.5
After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours.5
The administration of a single dose of binimetinib 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.5
- Volume of distribution
The geometric mean (CV%) of the apparent volume of distribution of binimetinib is 92 L (45%).5
- Protein binding
Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72.5
- 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.5
- 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.5
- Half-life
The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%).5
- Clearance
The apparent clearance (CL/F) of binimetinib is is 20.2 L/h (24%).5
- Adverse Effects
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Based on findings from animal reproduction studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of binimetinib during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.5
No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients.5
Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with binimetinib.5
Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats.5
- 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. Abemaciclib Abemaciclib may decrease the excretion rate of Binimetinib which could result in a higher serum level. 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. Acetylsalicylic acid The metabolism of Binimetinib can be increased when combined with Acetylsalicylic acid. Acyclovir The metabolism of Binimetinib can be decreased when combined with Acyclovir. Adagrasib The serum concentration of Binimetinib can be increased when it is combined with Adagrasib. 
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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 15 mg Oral Pfizer Canada Ulc 2021-07-05 Not applicable Canada 
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 
Categories
- ATC Codes
- L01EE03 — Binimetinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- 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
- 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]
- 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]
- Cancer.gov link [Link]
- FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
- FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
- Binimetinib [File]
- EMA assessment [File]
- External Links
- Human Metabolome Database
- HMDB0304890
- 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 Oral 15.000 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
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor signaling protein tyrosine phosphatase activity
- Specific Function
- Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones t...
- Gene Name
- MAP2K1
- Uniprot ID
- Q02750
- Uniprot Name
- Dual specificity mitogen-activated protein kinase kinase 1
- Molecular Weight
- 43438.65 Da
References
- FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- No
- 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
- No
- 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
References
- FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- Cavalieri G, Cilurzo G, Pettorosso L, Mansueto A, Laurini E, Pricl S: Biophysical and docking study on the interaction of anticancer drugs encorafenib and binimetinib with human serum albumin. Eur J Pharm Sci. 2023 Oct 1;189:106550. doi: 10.1016/j.ejps.2023.106550. Epub 2023 Jul 30. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
Drug created at October 20, 2016 21:06 / Updated at November 24, 2023 04:34