Identification
- Summary
Capmatinib is a kinase inhibitor targeting c-Met receptor tyrosine kinase in the treatment of non-small cell lung cancer with MET exon 14 skipping.
- Brand Names
- Tabrecta
- Generic Name
- Capmatinib
- DrugBank Accession Number
- DB11791
- Background
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 Capmatinib was approved by Health Canada on June 8, 2022.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Capmatinib (DB11791)
- 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
In the US, 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
Capmatinib is approved to treat adults with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations in Canada.6
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Metastatic non-small cell lung cancer •••••••••••• ••••• •••••• Treatment of Unresectable locally advanced nsclc •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism AHepatocyte growth factor receptor inhibitorHumans - 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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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
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Capmatinib can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Capmatinib. Acalabrutinib The serum concentration of Capmatinib can be increased when it is combined with Acalabrutinib. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Capmatinib. Acetaminophen The serum concentration of Capmatinib can be decreased when it is combined with Acetaminophen. - Food Interactions
- Take with or without food. Co-administration with high-fat meals slightly alters AUC, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Capmatinib hydrochloride C2A374O70X 1865733-40-9 COWBUPJEEDYWKD-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tabrecta Tablet, film coated 200 mg Oral Novartis Europharm Limited 2022-12-02 Not applicable EU 
Tabrecta Tablet, film coated 200 mg/1 Oral Novartis Pharmaceuticals Corporation 2020-05-06 Not applicable US 
Tabrecta Tablet 150 mg Oral Novartis 2022-09-16 Not applicable Canada 
Tabrecta Tablet, film coated 150 mg Oral Novartis Europharm Limited 2022-12-02 Not applicable EU Tabrecta Tablet, film coated 150 mg/1 Oral Novartis Pharmaceuticals Corporation 2020-05-06 Not applicable US
Categories
- ATC Codes
- L01EX17 — Capmatinib
- Drug Categories
- Acids, Carbocyclic
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Benzene Derivatives
- Benzoates
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- MATE 1 Inhibitors
- MATE 2 Inhibitors
- MATE 2-K Inhibitors
- MATE inhibitors
- Mesenchymal Epithelial Transition Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- 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
- Affected organisms
- Humans and other mammals
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
- 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. [Article]
- 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. [Article]
- FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
- FDA Approvals and Databases: FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer [Link]
- CaymanChem: Capmatinib MSDS [Link]
- Health Canada Approved Drug Products: TABRECTA (Capmatinib) Oral Tablets [Link]
- Cision PR Newswire: Health Canada approves (Pr)Tabrecta®: Targeted cancer therapy for locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations [Link]
- External Links
- PubChem Compound
- 25145656
- PubChem Substance
- 347828140
- ChemSpider
- 25069712
- BindingDB
- 50146167
- 2362165
- ChEMBL
- CHEMBL3188267
- ZINC
- ZINC000043195321
- Wikipedia
- Capmatinib
- FDA label
- Download (407 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Non-Small Cell Lung Carcinoma 1 3 Active Not Recruiting Health Services Research Soft Tissue Sarcoma 1 3 Completed Treatment Non-Small Cell Lung Carcinoma 1 3 Terminated Treatment Non-Small Cell Lung Carcinoma 1 2 Active Not Recruiting Treatment Non-Small Cell Lung Cancer (NSCLC) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 150 mg Tablet Oral 200 mg Tablet, film coated Oral 150 mg/1 Tablet, film coated Oral 200 mg/1 Tablet, film coated Oral 150 mg Tablet, film coated Oral 200 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8901123 No 2014-12-02 2029-05-20 US US8461330 No 2013-06-11 2027-11-19 US US7767675 No 2010-08-03 2027-11-19 US US8420645 No 2013-04-16 2031-06-05 US US10596178 No 2020-03-24 2035-07-22 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00529 mg/mL ALOGPS logP 3.04 ALOGPS logP 2.96 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 12.77 Chemaxon pKa (Strongest Basic) 4.55 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 85.07 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 125.27 m3·mol-1 Chemaxon Polarizability 42.1 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-0001900000-bca116a8268629fbd7a7 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-03dl-0006900000-ff69527bd6482e763c16 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-01q9-0009300000-ffc5be2c66a5fd11e63a Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-01q9-0009100000-cc0d292dc97f8c19fcf3 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0gx1-0209000000-e33c57ecdaa616993981 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-005c-1924000000-0b65551c76563b6fb6c4 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 194.95035 predictedDeepCCS 1.0 (2019) [M+H]+ 197.30833 predictedDeepCCS 1.0 (2019) [M+Na]+ 203.57965 predictedDeepCCS 1.0 (2019)
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
- 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
- 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
- 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
- FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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
- 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
- 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
- FDA Approved Drug Products: Tabrecta (capmatinib) oral tablets [Link]
Drug created at October 20, 2016 20:48 / Updated at June 10, 2022 17:10