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.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
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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMetastatic melanomaRegimen in combination with: Encorafenib (DB11718)••••••••••••••••••
Used in combination to treatMetastatic melanomaRegimen in combination with: Encorafenib (DB11718)••••••••••••••••••
Used in combination to treatMetastatic non-small cell lung cancerRegimen in combination with: Encorafenib (DB11718)•••••••••••••••••••••••
Used in combination to treatUnresectable melanomaRegimen in combination with: Encorafenib (DB11718)••••••••••••••••••
Used in combination to treatUnresectable melanomaRegimen in combination with: Encorafenib (DB11718)••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
ADual specificity mitogen-activated protein kinase kinase 2
inhibitor
Humans
ADual specificity mitogen-activated protein kinase kinase 1
inhibitor
Humans
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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Toxicity

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.
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.
AbemaciclibAbemaciclib may decrease the excretion rate of Binimetinib which could result in a higher serum level.
AbirateroneThe serum concentration of Binimetinib can be increased when it is combined with Abiraterone.
AbrocitinibThe serum concentration of Binimetinib can be increased when it is combined with Abrocitinib.
Food Interactions
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MektoviTablet15 mgOralPfizer Canada Ulc2021-07-05Not applicableCanada flag
MektoviTablet, film coated15 mgOralPierre Fabre Médicament2020-12-16Not applicableEU 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
L01EE03 — 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. 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]
  3. Cancer.gov link [Link]
  4. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
  5. FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
  6. Binimetinib [File]
  7. EMA assessment [File]
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
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4RecruitingTreatmentSolid Tumors1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentMelanoma3somestatusstop reasonjust information to hide
3CompletedTreatmentBRAF V600E-mutant Metastatic Colorectal Cancer1somestatusstop reasonjust information to hide
3CompletedTreatmentMetastatic or Unresectable Cutaneous Melanoma1somestatusstop reasonjust information to hide
3RecruitingTreatmentBiliary Tract Neoplasms1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral15 mg
TabletOral15.000 mg
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral15 MG
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/MSsplash10-0006-0000900000-611f9ca261be4b64ea83
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-01dr-0009800000-49b4276f279db04bc60b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014l-0009400000-c0ead1fc64a3cdaebd2d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-5009300000-944283b5294b7bcd2110
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-06ri-0049100000-04fe4b0a75a92e3ebe86
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9000000000-308ba3122a7cc4b1a574
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-184.66072
predicted
DeepCCS 1.0 (2019)
[M+H]+187.01872
predicted
DeepCCS 1.0 (2019)
[M+Na]+194.30202
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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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]
  2. FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
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
  1. 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
  1. FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
  2. FDA label [File]
  3. EMA assessment report [File]
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
  1. FDA Approved Drug Products: MEKTOVI® (binimetinib) tablets, for oral use [Link]
  2. EMA assessment report [File]
  3. FDA label, Binimetinib [File]
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
  1. 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
  1. 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
  1. 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
  1. 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