Identification

Name
Capmatinib
Accession Number
DB11791
Description

Capmatinib is a small molecule kinase inhibitor targeted against c-Met (a.k.a. hepatocyte growth factor receptor [HGFR]), a receptor tyrosine kinase that, in healthy humans, activates signaling cascades involved in organ regeneration and tissue repair.2 Aberrant c-Met activation - via mutations, amplification, and/or overexpression - is known to occur in many types of cancer, and leads to overactivation of multiple downstream signaling pathways such as STAT3, PI3K/ATK, and RAS/MAPK.2 Mutations in MET have been detected in non-small cell lung cancer (NSCLC), and the prevalence of MET amplification in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-naive patients with NSCLC has been reported to be 1.4% - 21%.2 This co-occurrence has made c-Met a desirable target in the treatment of NSCLC.

Manufactured by Novartis and marketed under the brand name Tabrecta, capmatinib was granted accelerated approval by the FDA on May 6, 2020,4 for the treatment of NSCLC in patients whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping.3 The presence of the mutation must be confirmed by an FDA-approved test, such as the FoundationOne CDx assay (manufactured by Foundation Medicine, Inc.), which was approved by the FDA on the same day.4 As this indication was granted under an accelerated approval, its continued approval is contingent upon verification of capmatinib's benefit in confirmatory trials.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 412.428
Monoisotopic: 412.144787354
Chemical Formula
C23H17FN6O
Synonyms
  • Capmatinib
External IDs
  • INC-280
  • INC280
  • INCB 28060
  • INCB-28060
  • INCB-28060 FREE BASE
  • INCB28060

Pharmacology

Indication

Capmatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.3

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Capmatinib inhibits the overactivity of c-Met, a receptor tyrosine kinase encoded by the MET proto-oncogene.3 Mutations in MET are involved in the proliferation of many cancers, including non-small cell lung cancer (NSCLC).3,2

Capmatinib may cause photosensitivity reactions in patients following ultraviolet (UV) exposure - patients undergoing therapy with capmatinib should be advised to use sunscreen and protective clothing to limit exposure to UV radiation.3 Instances of interstitial lung disease/pneumonitis, which can be fatal, occurred in patients being treated with capmatinib. Patients presenting with signs or symptoms of lung disease (e.g. cough, dyspnea, fever) should have capmatinib immediately withheld, and capmatinib should be permanently discontinued if no other feasible causes of the lung-related symptoms are identified.3

Mechanism of action

Aberrant activation of c-Met has been documented in many cancers, including non-small cell lung cancer (NSCLC).2 Mutations that result in the skipping of MET exon 14 lead to the formation of a mutant c-Met with a missing regulatory domain - these mutant proteins have a reduced ability to negatively regulate, leading to a pathological increase in their downstream activity.3

Capmatinib inhibits the phosphorylation of both wild-type and mutant variants of c-Met triggered by the binding of its endogenous ligand, hepatocyte growth factor - in doing so, it prevents c-Met-mediated phosphorylation of downstream signaling proteins, as well as the proliferation and survival of c-Met-dependent tumor cells.3

TargetActionsOrganism
AHepatocyte growth factor receptor
inhibitor
Humans
Absorption

The oral bioavailability of capmatinib is estimated to be >70%.3 Following oral administration, maximum plasma concentrations are achieved within 1 to 2 hours (Tmax).3 Co-administration with a high-fat meal increased capmatinib AUC by 46% with no change in Cmax (as compared to fasted conditions), and co-administration with a low-fat meal had no clinically meaningful effects on exposure.3

Volume of distribution

The apparent volume of distribution at steady-state is 164 L.3

Protein binding

Plasma protein binding is approximately 96% and is independent of drug serum concentration.3

Metabolism

Capmatinib undergoes metabolism primarily via CYP3A4 and aldehyde oxidase.3 Specific biotransformation pathways and metabolic products have yet to be elucidated.

Route of elimination

Following oral administration of radiolabeled capmatinib, approximately 78% of the radioactivity is recovered in feces, of which ~42% is unchanged parent drug, and 22% is recovered in the urine, of which a negligible amount remains unchanged parent drug.3

Half-life

The elimination half-life is 6.5 hours.3

Clearance

The mean apparent clearance of capmatinib at steady-state is 24 L/h.3

Adverse Effects
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Toxicity

Data regarding toxicity and overdose of capmatinib are limited. Embryo-fetal toxicity has been documented in animal models - both males and females using capmatinib should use effective contraception throughout the course of therapy and for 1 week following cessation of therapy.3

Affected organisms
  • Humans and other mammals
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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Capmatinib.
AbametapirThe serum concentration of Capmatinib can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Capmatinib.
AcalabrutinibThe serum concentration of Capmatinib can be increased when it is combined with Acalabrutinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Capmatinib.
AcetaminophenThe serum concentration of Capmatinib can be decreased when it is combined with Acetaminophen.
AcyclovirThe metabolism of Acyclovir can be decreased when combined with Capmatinib.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Capmatinib.
AgomelatineThe metabolism of Agomelatine can be decreased when combined with Capmatinib.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Capmatinib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with or without food. Co-administration with high-fat meals slightly alters AUC, but not to a clinically significant extent.

Products

Product Ingredients
IngredientUNIICASInChI Key
Capmatinib hydrochlorideC2A374O70X1865733-40-9COWBUPJEEDYWKD-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TabrectaTablet, film coated150 mg/1OralNovartis Pharmaceuticals Corporation2020-05-06Not applicableUS flag
TabrectaTablet, film coated200 mg/1OralNovartis Pharmaceuticals Corporation2020-05-06Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinolines and derivatives. These are compounds containing a quinoline moiety, which consists of a benzene ring fused to a pyrimidine ring to form benzo[b]azabenzene.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Not Available
Direct Parent
Quinolines and derivatives
Alternative Parents
2-halobenzoic acids and derivatives / Benzamides / Imidazo[1,2-a][1,2,4]triazines / Benzoyl derivatives / Fluorobenzenes / N-substituted imidazoles / 1,2,4-triazines / Aryl fluorides / Pyridines and derivatives / Vinylogous halides
show 8 more
Substituents
1,2,4-triazine / 2-halobenzoic acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzamide / Benzenoid / Benzoic acid or derivatives
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
TY34L4F9OZ
CAS number
1029712-80-8
InChI Key
LIOLIMKSCNQPLV-UHFFFAOYSA-N
InChI
InChI=1S/C23H17FN6O/c1-25-22(31)18-6-5-16(11-19(18)24)21-13-28-23-27-12-17(30(23)29-21)10-14-4-7-20-15(9-14)3-2-8-26-20/h2-9,11-13H,10H2,1H3,(H,25,31)
IUPAC Name
2-fluoro-N-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-b][1,2,4]triazin-2-yl}benzamide
SMILES
CNC(=O)C1=C(F)C=C(C=C1)C1=NN2C(CC3=CC4=C(C=C3)N=CC=C4)=CN=C2N=C1

References

General References
  1. Saad KM, Shaker ME, Shaaban AA, Abdelrahman RS, Said E: The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity. Int Immunopharmacol. 2020 Apr;81:106292. doi: 10.1016/j.intimp.2020.106292. Epub 2020 Feb 14. [PubMed:32062076]
  2. Kim S, Kim TM, Kim DW, Kim S, Kim M, Ahn YO, Keam B, Heo DS: Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib. Cancer Res Treat. 2019 Jul;51(3):951-962. doi: 10.4143/crt.2018.052. Epub 2018 Oct 10. [PubMed:30309221]
  3. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
  4. FDA Approvals and Databases: FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer [Link]
  5. CaymanChem: Capmatinib MSDS [Link]
PubChem Compound
25145656
PubChem Substance
347828140
ChemSpider
25069712
BindingDB
50146167
RxNav
2362165
ChEMBL
CHEMBL3188267
ZINC
ZINC000043195321
Wikipedia
Capmatinib
FDA label
Download (407 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Not Yet RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
3RecruitingHealth Services ResearchSoft Tissue Sarcoma (STS)1
2Active Not RecruitingTreatmentAdvanced Hepatocellular Carcinoma With c-MET Dysregulation1
2Active Not RecruitingTreatmentMalignant Non-small Cell Neoplasm of Lung Stage IV1
2Active Not RecruitingTreatmentMelanoma1
2Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)2
2CompletedTreatmentAdenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma1
2CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2Not Yet RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2RecruitingTreatmentAdvanced Solid Tumors Which Are cMET-dependent1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral150 mg/1
Tablet, film coatedOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8901123No2009-05-202029-05-20US flag
US8461330No2007-11-192027-11-19US flag
US7767675No2007-11-192027-11-19US flag
US8420645No2011-06-052031-06-05US flag
US10596178No2015-07-222035-07-22US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00529 mg/mLALOGPS
logP3.04ALOGPS
logP2.96ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.77ChemAxon
pKa (Strongest Basic)4.55ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area85.07 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity125.27 m3·mol-1ChemAxon
Polarizability42.1 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including...
Gene Name
MET
Uniprot ID
P08581
Uniprot Name
Hepatocyte growth factor receptor
Molecular Weight
155540.035 Da
References
  1. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xanthine dehydrogenase activity
Specific Function
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N-methylphthalazinium, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal...
Gene Name
AOX1
Uniprot ID
Q06278
Uniprot Name
Aldehyde oxidase
Molecular Weight
147916.735 Da
References
  1. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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: Tabrecta (capmatinib) oral tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Based on in vitro studies.
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: Tabrecta (capmatinib) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Based on in vitro studies.
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Based on in vitro studies.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Direct evidence of inhibition is lacking - co-administration with rosuvastatin (a BCRP substrate), however, increased rosuvastatin AUC by ~100% and Cmax by ~200%.
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: Tabrecta (capmatinib) oral tablets [Link]

Drug created on October 20, 2016 14:48 / Updated on June 12, 2020 10:53

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