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Identification
NameTrametinib
Accession NumberDB08911
TypeSmall Molecule
GroupsApproved
Description

Trametinib dimethyl sulfoxide is a kinase inhibitor. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. FDA approved on May 29, 2013.

Structure
Thumb
Synonyms
SynonymLanguageCode
GSK 1120212Not AvailableNot Available
JTP 74057Not AvailableNot Available
Trametinib Dimethyl Sulfoxide Not AvailableNot Available
TrametinibumNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mekinisttablet, film coated2 mgoralGlaxo Smith Kline Llc2013-06-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Mekinisttablet, film coated.5 mgoralGlaxo Smith Kline Llc2013-06-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Mekinisttablet, film coated1 mgoralGlaxo Smith Kline Llc2013-06-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Mekinisttablet0.5 mgoralGlaxosmithkline IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Mekinisttablet2 mgoralGlaxosmithkline IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number871700-17-3
WeightAverage: 615.3948
Monoisotopic: 615.077875874
Chemical FormulaC26H23FIN5O4
InChI KeyLIRYPHYGHXZJBZ-UHFFFAOYSA-N
InChI
InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
IUPAC Name
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide
SMILES
CN1C(=O)C(C)=C2N(C(=O)N(C3CC3)C(=O)C2=C1NC1=CC=C(I)C=C1F)C1=CC(NC(C)=O)=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyridopyrimidines. These are compounds containing a pyridopyrimidine, which consists of a pyridine fused to a pyrimidine. Pyridine is 6-membered ring consisting of five carbon atoms and a nitrogen atom. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPyridopyrimidines
Sub ClassNot Available
Direct ParentPyridopyrimidines
Alternative Parents
Substituents
  • N-arylamide
  • Pyridopyrimidine
  • Acetanilide
  • Methylpyridine
  • Pyrimidone
  • Pyridinone
  • Iodobenzene
  • Halobenzene
  • Fluorobenzene
  • Aminopyridine
  • Benzenoid
  • Pyrimidine
  • Pyridine
  • Monocyclic benzene moiety
  • Aryl iodide
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Acetamide
  • Vinylogous amide
  • Urea
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organoiodide
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationTrametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.
PharmacodynamicsWhen 1 mg and 2 mg trametinib is given to patients with BRAF V600 mutation-positive melanoma, an inhibition of phosphorylated ERK and Ki67, and an increase in p27 was observed. These changes indicate that trametinib caused a decrease in cell proliferation and an increase in apoptosis, respectively.
Mechanism of actionTrametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2.
AbsorptionTrametinib is rapidly absorbed. When an oral administration of trametinib was given to patients with BRAF V600 mutation-positive melanoma, peak plasma concentration occurred 1.5 hours post-dose (Tmax). A single 2 mg oral dose has a bioavailability of 72%. When a dose of 2mg/day is given, the peak plasma concentration (Cmax) is 22.2 ng/mL.
Volume of distribution

Apparent volume of distribution (Vd/F) = 214 L

Protein binding97.4% bound to human plasma proteins.
Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. The cytochrome P450 enzyme system is not involved with the metabolism of trametinib. The predominant circulating component in the plasma is the parent compound.

Route of elimination80% of the dose is excreted in the feces. <20% of the dose is excreted in the urine with <0.1% of the excreted dose in the form of the parent compound.
Half lifeElimination half-life = 3.9-4.8 days.
Clearance

Apparent clearance = 4.9 L/h.

ToxicityMost common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9733
Blood Brain Barrier+0.8217
Caco-2 permeable-0.5193
P-glycoprotein substrateNon-substrate0.5945
P-glycoprotein inhibitor INon-inhibitor0.6449
P-glycoprotein inhibitor IINon-inhibitor0.8622
Renal organic cation transporterNon-inhibitor0.899
CYP450 2C9 substrateNon-substrate0.7215
CYP450 2D6 substrateNon-substrate0.8232
CYP450 3A4 substrateSubstrate0.5735
CYP450 1A2 substrateNon-inhibitor0.8599
CYP450 2C9 substrateNon-inhibitor0.5775
CYP450 2D6 substrateNon-inhibitor0.9521
CYP450 2C19 substrateNon-inhibitor0.8769
CYP450 3A4 substrateNon-inhibitor0.836
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9337
Ames testAMES toxic0.5498
CarcinogenicityNon-carcinogens0.8078
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3412 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9539
hERG inhibition (predictor II)Non-inhibitor0.6602
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral0.5 mg
Tabletoral2 mg
Tablet, film coatedoral.5 mg
Tablet, film coatedoral1 mg
Tablet, film coatedoral2 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States73784232013-05-292025-09-13
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0307 mg/mLALOGPS
logP3.45ALOGPS
logP3.18ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)12.6ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area102.06 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity156.38 m3·mol-1ChemAxon
Polarizability55.43 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed
External Links
ATC CodesL01XE25
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (517 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AripiprazoleCYP3A4 Inducers may decrease the serum concentration of ARIPiprazole.
DabrafenibTrametinib may enhance the adverse/toxic effect of Dabrafenib.
HydrocodoneCYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone.
SaxagliptinCYP3A4 Inducers may decrease the serum concentration of Saxagliptin.
Food Interactions
  • When taken with a high-fat, high-calorie meal, AUC and Cmax decreased. Tmax was also prolonged compared to fasted conditions.

Targets

1. Dual specificity mitogen-activated protein kinase kinase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 1 Q02750 Details

References:

  1. FDA label
  2. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed

2. Dual specificity mitogen-activated protein kinase kinase 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 2 P36507 Details

References:

  1. FDA label
  2. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed

Enzymes

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. FDA label

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA label

Comments
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Drug created on June 24, 2013 15:36 / Updated on September 16, 2013 18:11