Trametinib

Identification

Summary

Trametinib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.

Brand Names
Mekinist
Generic Name
Trametinib
DrugBank Accession Number
DB08911
Background

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 4.

The U.S. Food and Drug Administration approved Dabrafenib(Tafilnar) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive) 3.

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health (NIH) estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for approximately 1 to 2 percent of all thyroid cancers 3.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 615.3948
Monoisotopic: 615.077875874
Chemical Formula
C26H23FIN5O4
Synonyms
  • Tramétinib
  • Trametinib
  • Trametinibum
External IDs
  • GSK 1120212
  • GSK-1120212
  • GSK1120212
  • JTP 74057
  • JTP-74057

Pharmacology

Indication

Trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [FDA].

In May 2018, it was approved for use with Dabrafenib for the treatment of treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene 3.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Trametinib is an anticancer agent which causes apoptosis (or programmed cell death) and inhibits cell proliferation, which are both important in the treatment of malignancies 2.

Mechanism of action

Trametinib 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 Label.

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

Trametinib is readily 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 Label.

Volume of distribution

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

Protein binding

97.4% bound to human plasma proteins Label

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 drug Label.

Route of elimination

80% 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 Label.

Half-life

Elimination half-life = 3.9-4.8 days Label.

Clearance

Apparent clearance = 4.9 L/h Label

Adverse Effects
Adverseeffects
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Toxicity

Most common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema Label.

The most common adverse reactions (≥20%) for Tafinlar in combination with Trametinib are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia Label.

The following is a list of toxicities that may occur with the combination of Dabrafenib and Trametinib:

New primary malignancies: These may occur when Tafinlar is administered as a single agent or in combination with Trametinib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of TAFINLAR or the combination therapy. Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors Label.

Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding Label.

Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving the drug combination Label.

Cardiomyopathy: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter Label.

Ocular toxicities: Perform an ophthalmologic evaluation for any visual disturbances Label.

Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib Label.

Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite the interruption of TAFINLAR Label.

Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia Label.

Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia Label.

Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used 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
AbacavirAbacavir may decrease the excretion rate of Trametinib which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Trametinib.
AcetaminophenAcetaminophen may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Trametinib which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Trametinib which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcrivastineTrametinib may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Trametinib which could result in a higher serum level.
Interactions
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Food Interactions
  • Take separate from meals. Take at least one hour before or two hours after a meal.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Trametinib dimethyl sulfoxideBSB9VJ5TUT1187431-43-1OQUFJVRYDFIQBW-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MekinistTablet, film coated.5 mg/1OralNovartis Pharmaceuticals Corporation2016-03-17Not applicableUS flag
MekinistTablet2 mgOralNovartis2013-08-28Not applicableCanada flag
MekinistTablet, film coated1 mg/1OralGlaxoSmithKline Manufacturing SpA2013-06-17Not applicableUS flag
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2016-10-06Not applicableEU flag
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag
MekinistTablet, film coated0.5 mg/1OralGlaxosmithkline Inc2013-06-172016-12-31US flag
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag
MekinistTablet, film coated1 mg/1OralGlaxoSmithKline LLC2013-06-172013-05-29US flag
MekinistTablet0.5 mgOralNovartis2013-08-28Not applicableCanada flag
MekinistTablet, film coated0.5 mg/1OralGlaxoSmithKline Manufacturing SpA2013-06-17Not applicableUS flag

Categories

ATC Codes
L01XE25 — Trametinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridopyrimidines
Sub Class
Not Available
Direct Parent
Pyridopyrimidines
Alternative Parents
Acetanilides / N-acetylarylamines / Aniline and substituted anilines / Aminopyridines and derivatives / Pyrimidones / Pyridinones / Fluorobenzenes / Methylpyridines / Iodobenzenes / Aryl fluorides
show 16 more
Substituents
Acetamide / Acetanilide / Amine / Amino acid or derivatives / Aminopyridine / Anilide / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, organoiodine compound, acetamides, aromatic amine, cyclopropanes, ring assembly, pyridopyrimidine (CHEBI:75998)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
33E86K87QN
CAS number
871700-17-3
InChI Key
LIRYPHYGHXZJBZ-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

References

General References
  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. [Article]
  2. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA: Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):773-81. doi: 10.1016/S1470-2045(12)70270-X. Epub 2012 Jul 16. [Article]
  3. FDA approves new uses for two drugs administered together for the treatment of BRAF-positive anaplastic thyroid cancer [Link]
  4. Drugs@FDA: FDA Approved Drug Products [Link]
KEGG Drug
D10175
PubChem Compound
11707110
PubChem Substance
175427149
ChemSpider
9881833
RxNav
1425099
ChEBI
75998
ChEMBL
CHEMBL2103875
ZINC
ZINC000043100709
PharmGKB
PA166115364
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trametinib
FDA label
Download (517 KB)
MSDS
Download (120 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentAnaplastic Astrocytoma (AA) / Anaplastic Ganglioglioma / Anaplastic Oligodendroglioma (AO) / Angiocentric glioma / Astrocytomas / Central Neurocytoma / Cerebellar Liponeurocytoma / Chordoid Glioma of Third Ventricle / Desmoplastic Infantile Astrocytoma and Ganglioglioma / Diffuse Astrocytoma / Dysplastic Gangliocytoma of Cerebrellum / Extraventricular Neurocytoma / Gangliocytoma / Ganglioglioma / Giant Cell Astrocytoma / Glioblastoma Multiforme (GBM) / Neurofibromatosis Type 1 (NF1) / Oligodendroglioma, Childhood / Papillary Glioneuronal Tumor / Pilocytic Astrocytoma / Pleomorphic Xantho-Astrocytoma / Pleomorphic Xanthoastrocytoma, Anaplastic / Rosette-forming Glioneurona Tumor1
4RecruitingTreatmentHigh Grade Glioma (HGG) / Malignant Melanoma of Skin / Non-Small Cell Lung Carcinoma (NSCLC) / Rare Cancers / Tumors, Solid1
3Active Not RecruitingTreatmentMalignant Melanoma of Skin2
3Active Not RecruitingTreatmentMelanoma, Malignant1
3CompletedTreatmentMalignant Melanoma of Skin3
3Not Yet RecruitingTreatmentDifferentiated Thyroid Cancer (DTC)1
3RecruitingHealth Services ResearchSoft Tissue Sarcoma (STS)1
3RecruitingTreatmentMetastatic Melanoma / Recurrent Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Unresectable Cutaneous Melanoma1
2Active Not RecruitingTreatmentAdenocarcinomas / Malignant Neoplasm of Pancreas1
2Active Not RecruitingTreatmentAdvanced Lymphomas / Advanced Malignant Solid Neoplasm / Hematopoietic and Lymphoid Cell Neoplasm / Refractory Lymphomas / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral0.5 mg
TabletOral1 mg
TabletOral2 mg
Tablet, film coatedOral.5 mg/1
Tablet, film coatedOral0.5 mg/1
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral1 MG
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral2 MG
Tablet, film coatedOral0.5 mg
Tablet, coatedOral2 mg
Tablet, film coatedOral
Tablet, coatedOral0.5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8703781No2014-04-222030-10-15US flag
US8835443No2014-09-162025-09-13US flag
US9271941No2016-03-012032-01-28US flag
US9155706No2015-10-132032-01-28US flag
US7378423No2008-05-272025-09-13US flag
US8580304No2013-11-122032-01-28US flag
US8952018No2015-02-102030-10-15US flag
US9399021No2016-07-262032-01-28US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)293-303 MSDS
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.5775
CYP450 2D6 inhibitorNon-inhibitor0.9521
CYP450 2C19 inhibitorNon-inhibitor0.8769
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. 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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. 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. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [Article]
  2. Drugs@FDA: FDA Approved Drug Products [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Drugs@FDA: FDA Approved Drug Products [Link]

Drug created on June 24, 2013 21:36 / Updated on September 28, 2021 07:54