Binimetinib

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
Thumb
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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
UInterleukin-6Not AvailableHumans
UTumor necrosis factorNot AvailableHumans
UInterleukin-1 betaNot AvailableHumans
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
Adverseeffects
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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.

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.
DrugInteraction
AbametapirThe serum concentration of Binimetinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Binimetinib can be increased when combined with Abatacept.
AbirateroneThe serum concentration of Binimetinib can be increased when it is combined with Abiraterone.
AcenocoumarolThe metabolism of Binimetinib can be decreased when combined with Acenocoumarol.
AcetaminophenThe metabolism of Binimetinib can be decreased when combined with Acetaminophen.
AcyclovirThe metabolism of Binimetinib can be decreased when combined with Acyclovir.
AdalimumabThe metabolism of Binimetinib can be increased when combined with Adalimumab.
AdenineThe metabolism of Binimetinib can be decreased when combined with Adenine.
AfatinibThe serum concentration of Binimetinib can be increased when it is combined with Afatinib.
AgomelatineThe metabolism of Binimetinib can be decreased when combined with Agomelatine.
Interactions
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Food Interactions
  • Take with or without food.

Products

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dosage, form, labeller, route of administration, and marketing period.
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MektoviTablet, film coated15 mgOralPierre Fabre Médicament2020-12-16Not applicableEU flag
MektoviTablet15 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
MektoviTablet, film coated15 mg/1OralArray BioPharma Inc.2018-06-27Not applicableUS flag
MektoviTablet, film coated15 mgOralPierre Fabre Médicament2020-12-16Not applicableEU flag

Categories

ATC Codes
L01XE41 — Binimetinib
Drug Categories
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
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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]
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
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBRAF V600E-mutant Metastatic Colorectal Cancer1
3Active Not RecruitingTreatmentLow Grade Serous Ovarian Cancer / Low-grade Serous Fallopian Tube Cancer / Low-grade Serous Peritoneal Cancer1
3Active Not RecruitingTreatmentMalignant Melanoma of Skin1
3CompletedTreatmentMetastatic or Unresectable Cutaneous Melanoma1
3RecruitingTreatmentMalignant Melanoma of Skin1
3RecruitingTreatmentMetastatic Colorectal Cancer (CRC) / Stage III Colorectal Cancer1
2Active Not RecruitingTreatmentAdvanced Lymphomas / Advanced Malignant Solid Neoplasm / Hematopoietic and Lymphoid Cell Neoplasm / Refractory Lymphomas / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma1
2Active Not RecruitingTreatmentBRAF or NRAS Mutant Metastatic Melanoma1
2Active Not RecruitingTreatmentBRAF V600E-mutant Metastatic Colorectal Cancer1
2Active Not RecruitingTreatmentMalignant Melanoma of Skin1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral15 mg
Tablet, film coatedOral15 MG
Tablet, film coatedOral15 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9314464No2016-04-192031-07-04US flag
US9850229No2017-12-262030-08-27US flag
US10005761No2018-06-262030-08-27US flag
US9593100No2017-03-142030-08-27US flag
US9980944No2018-05-292033-10-18US flag
US9598376No2017-03-212033-10-18US flag
US8193229No2012-06-052023-03-13US flag
US8513293No2013-08-202023-03-13US flag
US7777050No2010-08-172023-03-13US flag
US8178693No2012-05-152023-03-13US flag
US9562016No2017-02-072033-10-18US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0499 mg/mLALOGPS
logP3ALOGPS
logP3.81ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)10.26ChemAxon
pKa (Strongest Basic)5.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area88.41 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity98.02 m3·mol-1ChemAxon
Polarizability38.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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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
  1. 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
  1. 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
  1. Cancer.gov link [Link]
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
  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. [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
  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. [Article]

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
  1. FDA label [File]
  2. EMA assessment report [File]
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
  1. EMA assessment report [File]
  2. FDA label, Binimetinib [File]
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 on October 20, 2016 21:06 / Updated on July 28, 2021 15:00