Identification
- Summary
Tepotinib is an oral tyrosine kinase inhibitor targeted against MET for the treatment of metastatic non-small cell lung cancer in patients exhibiting MET exon 14 skipping mutations.
- Brand Names
- Tepmetko
- Generic Name
- Tepotinib
- DrugBank Accession Number
- DB15133
- Background
Tepotinib is a MET tyrosine kinase inhibitor intended to treat a variety of MET-overexpressing solid tumors.6 It was originally developed in partnership between EMD Serono and the University of Texas M.D. Anderson Cancer Center in 2009 and has since been investigated in the treatment of neuroblastoma,5 gastric cancers,2 non-small cell lung cancer, and hepatocellular carcinoma.6 MET is a desirable target in the treatment of certain solid tumors as it appears to play a critical role, both directly and indirectly, in the growth and proliferation of tumors in which it is overexpressed and/or mutated.
Tepotinib was first approved in Japan in March 2020 for the treatment of non-small cell lung cancers (NSCLC) with MET alterations, and was subsequently granted accelerated approval by the US FDA in February 2021, under the brand name Tepmetko, for the treatment of adult patients with metastatic NSCLC and MET exon 14 skipping alterations.7,9 It is the first oral MET-targeted tyrosine kinase inhibitor to allow for once-daily dosing,9 an advantage that may aid in easing the pill burden often associated with chemotherapeutic regimens.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tepotinib (DB15133)
- Weight
- Average: 492.583
Monoisotopic: 492.227374166 - Chemical Formula
- C29H28N6O2
- Synonyms
- Tepotinib
- External IDs
- EMD 1214063
- EMD-1214063
- EMD1214063
- MSC-2156119
- MSC-2156119J
- MSC2156119
- WHO 9934
Pharmacology
- Indication
Tepotinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) who have mesenchymal-epithelial transition (MET) exon 14 skipping alterations.7
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC50 of approximately 1.7 nmol/L.6 It has a moderate duration of action necessitating once-daily administration.7
Tepotinib has been associated with the development of interstitial lung disease (ILD)/pneumonitis, which can sometimes be fatal.7 Patients should be monitored closely for signs of new or worsening respiratory symptoms (e.g. dyspnea, cough), and treatment with tepotinib should be immediately withheld if ILD/pneumonitis is suspected. If no other potential causes of ILD/pneumonitis are identified, therapy with tepotinib should be suspended indefinitely.7
- Mechanism of action
Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase found overexpressed and/or mutated in a variety of tumor types, thus making it a desirable target in their treatment. MET plays a critical role in the proliferation, survival, invasion, and mobilization of tumor cells, and aberrant MET activation is thought to contribute to the development of more aggressive cancers with poorer prognoses.2
Tepotinib is a kinase inhibitor directed against MET, including variants with exon 14 skipping - it inhibits MET phosphorylation and subsequent downstream signaling pathways in order to inhibit tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells.7 Tepotinib has also been observed to down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (e.g. MMP7, COX-2, WNT1, MUC5B, and c-MYC) and upregulate the expression of EMT-suppressing genes (e.g. MUC5AC, MUC6, GSK3β, and E-cadherin) in c-MET-amplified gastric cancer cells,2 suggesting that the tumor-suppressing activity of tepotinib is driven, at least in part, by the negative regulation of c-MET-induced EMT. It has also been shown to inhibit melatonin 1B and nischarin at clinically relevant concentrations, though the relevance of this activity in regards to tepotinib's mechanism of action is unclear.7
Target Actions Organism AHepatocyte growth factor receptor inhibitorHumans UNischarin inhibitorHumans UMelatonin receptor type 1B inhibitorHumans - Absorption
The absolute bioavailability of tepotinib following oral administration is approximately 72%.7,3 At the recommended dosage of 450mg once daily, the median Tmax is 8 hours and the mean steady-state Cmax and AUC0-24h were 1,291 ng/mL and 27,438 ng·h/mL, respectively.7
Co-administration with a high-fat, high-calorie meal increases the AUC and Cmax of tepotinib by approximately 1.6-fold and 2-fold, respectively.7
- Volume of distribution
The mean apparent volume of distribution is 1,038L.7
- Protein binding
Tepotinib is approximately 98% protein-bound in plasma,7 primarily to serum albumin and alpha-1-acid glycoprotein.3 Plasma protein binding is independent of drug concentration at clinically relevant exposures.7
- Metabolism
Tepotinib is metabolized primarily by CYP3A4 and CYP2C8,7 with some apparent contribution by unspecified UGT enzymes.3 The metabolite M506 is the major circulating metabolite, comprising approximately 40.4% of observed drug material in plasma,7 while the M668 glucuronide metabolite has been observed in plasma at much lower quantities (~4% of an orally administered dose).3 A total of 10 phase I and phase II metabolites have been detected following tepotinib administration, most of which are excreted in the feces.3
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- Route of elimination
Following oral administration, approximately 85% of the given dose is excreted in the feces with the remainder excreted in the urine.7 Unchanged parent drug accounts for roughly half of the dose excreted in the feces,7,3 with the remainder comprising the demethylated M478 metabolite, a glucuronide metabolite, the racemic M506 metabolite, and some minor oxidative metabolites.3 Unchanged parent drug also accounts for roughly half of the dose excreted in the urine, with the remainder comprising a glucuronide metabolite and a pair of N-oxide diastereomer metabolites.3
- Half-life
Following oral administration, the half-life of tepotinib is approximately 32 hours.7
- Clearance
The apparent clearance of tepotinib is 23.8 L/h.7
- Adverse Effects
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There are no data regarding overdosage of tepotinib. Symptoms of overdose are likely to be consistent with tepotinib's adverse effect profile and may therefore involve significant gastrointestinal symptoms, musculoskeletal pain, and laboratory abnormalities.7 Treatment of overdose should involve symptomatic and supportive measures. In the event of overdose, dialysis is unlikely to be of benefit given the high degree of plasma protein binding exhibited by tepotinib.
- 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 softwareAbaloparatide The therapeutic efficacy of Abaloparatide can be decreased when used in combination with Tepotinib. Abametapir The serum concentration of Tepotinib can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Tepotinib. Abrocitinib The serum concentration of Tepotinib can be increased when it is combined with Abrocitinib. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Tepotinib. Afatinib The serum concentration of Tepotinib can be increased when it is combined with Afatinib. Allopurinol Tepotinib may decrease the excretion rate of Allopurinol which could result in a higher serum level. Alpelisib The serum concentration of Alpelisib can be increased when it is combined with Tepotinib. Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with Tepotinib. Amiodarone The serum concentration of Tepotinib can be increased when it is combined with Amiodarone. 
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- Take with food. Co-administration with a meal improves the absorption of tepotinib.
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 Tepotinib hydrochloride VY5YX2TQ1F 1946826-82-9 KZVOMLRKFJUTLK-UHFFFAOYSA-N - International/Other Brands
- Tepmetko (EMD Serono)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tepmetko Tablet 225 mg/1 Oral EMD Serono, Inc. 2021-02-03 Not applicable US 
Tepmetko Tablet, film coated 225 mg Oral Merck Europe B.V. 2022-05-11 Not applicable EU 
Tepmetko Tablet 225 mg Oral Emd Serono, A Division Of Emd Inc., Canada 2021-10-07 Not applicable Canada 
Categories
- Drug Categories
- Antineoplastic Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- Mesenchymal Epithelial Transition Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-met, antagonists & inhibitors
- Tyrosine Kinase Inhibitors
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 1IJV77EI07
- CAS number
- 1100598-32-0
- InChI Key
- AHYMHWXQRWRBKT-UHFFFAOYSA-N
- InChI
- InChI=1S/C29H28N6O2/c1-34-12-10-21(11-13-34)20-37-26-17-31-29(32-18-26)25-7-3-5-23(15-25)19-35-28(36)9-8-27(33-35)24-6-2-4-22(14-24)16-30/h2-9,14-15,17-18,21H,10-13,19-20H2,1H3
- IUPAC Name
- 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile
- SMILES
- CN1CCC(COC2=CN=C(N=C2)C2=CC(CN3N=C(C=CC3=O)C3=CC(=CC=C3)C#N)=CC=C2)CC1
References
- General References
- Abdelhameed AS, Attwa MW, Kadi AA: Identification of Iminium Intermediates Generation in the Metabolism of Tepotinib Using LC-MS/MS: In Silico and Practical Approaches to Bioactivation Pathway Elucidation. Molecules. 2020 Oct 28;25(21). pii: molecules25215004. doi: 10.3390/molecules25215004. [Article]
- Sohn SH, Sul HJ, Kim B, Kim BJ, Kim HS, Zang DY: Tepotinib Inhibits the Epithelial-Mesenchymal Transition and Tumor Growth of Gastric Cancers by Increasing GSK3beta, E-Cadherin, and Mucin 5AC and 6 Levels. Int J Mol Sci. 2020 Aug 21;21(17). pii: ijms21176027. doi: 10.3390/ijms21176027. [Article]
- Johne A, Scheible H, Becker A, van Lier JJ, Wolna P, Meyring M: Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers. Invest New Drugs. 2020 Oct;38(5):1507-1519. doi: 10.1007/s10637-020-00926-1. Epub 2020 Mar 27. [Article]
- Wu ZX, Teng QX, Cai CY, Wang JQ, Lei ZN, Yang Y, Fan YF, Zhang JY, Li J, Chen ZS: Tepotinib reverses ABCB1-mediated multidrug resistance in cancer cells. Biochem Pharmacol. 2019 Aug;166:120-127. doi: 10.1016/j.bcp.2019.05.015. Epub 2019 May 9. [Article]
- Scorsone K, Zhang L, Woodfield SE, Hicks J, Zage PE: The novel kinase inhibitor EMD1214063 is effective against neuroblastoma. Invest New Drugs. 2014 Oct;32(5):815-24. doi: 10.1007/s10637-014-0107-4. Epub 2014 May 16. [Article]
- Markham A: Tepotinib: First Approval. Drugs. 2020 Jun;80(8):829-833. doi: 10.1007/s40265-020-01317-9. [Article]
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
- CaymanChem: Tepotinib MSDS [Link]
- PR Newswire: FDA Approves TEPMETKO® as the First and Only Once-daily Oral MET Inhibitor for Patients with Metastatic NSCLC with METex14 Skipping Alterations [Link]
- External Links
- ChemSpider
- 28637823
- BindingDB
- 50065457
- 2477103
- ChEMBL
- CHEMBL3402762
- ZINC
- ZINC000043202335
- PDBe Ligand
- 3E8
- Wikipedia
- C-Met_inhibitor
- PDB Entries
- 4r1v
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 2 Active Not Recruiting Treatment Advanced (Stage IIIB/IV) Non-small Cell Lung Cancer (NSCLC) With MET Exon 14 (METex14) Skipping Alterations or MET Amplification 1 2 Active Not Recruiting Treatment Neoplasms, Colorectal 1 2 Recruiting Treatment MET Amplification / MET exon 14 skipping mutation / Solid Tumors 1 2 Recruiting Treatment Non-Small Cell Lung Carcinoma (NSCLC) 1 1 Active Not Recruiting Treatment Healthy Subjects (HS) 1 1 Completed Other Healthy Subjects (HS) 5 1 Completed Other Hepatic Impairment 1 1 Completed Treatment Healthy Subjects (HS) 1 1 Completed Treatment Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available 1 1 Completed Treatment Solid Tumors 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 225 mg Tablet Oral 225 mg/1 Tablet, film coated Oral 225 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8658643 No 2014-02-25 2028-07-04 US US8927540 No 2015-01-06 2028-07-21 US US9403799 No 2016-08-02 2028-07-04 US US8580781 No 2013-11-12 2030-03-19 US US8921357 No 2014-12-30 2028-05-30 US US9062029 No 2015-06-23 2028-07-04 US US8329692 No 2012-12-11 2029-10-30 US US9284300 No 2016-03-15 2028-04-29 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source pKa 9.5 FDA Label - Predicted Properties
Property Value Source logP 4 ChemAxon pKa (Strongest Basic) 9.13 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 7 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 94.71 Å2 ChemAxon Rotatable Bond Count 7 ChemAxon Refractivity 154.74 m3·mol-1 ChemAxon Polarizability 54.7 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not 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
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Phosphatidylinositol binding
- Specific Function
- Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-si...
- Gene Name
- NISCH
- Uniprot ID
- Q9Y2I1
- Uniprot Name
- Nischarin
- Molecular Weight
- 166627.105 Da
References
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Melatonin receptor activity
- Specific Function
- High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that ...
- Gene Name
- MTNR1B
- Uniprot ID
- P49286
- Uniprot Name
- Melatonin receptor type 1B
- Molecular Weight
- 40187.895 Da
References
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [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: Tepmetko (tepotinib) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Johne A, Scheible H, Becker A, van Lier JJ, Wolna P, Meyring M: Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers. Invest New Drugs. 2020 Oct;38(5):1507-1519. doi: 10.1007/s10637-020-00926-1. Epub 2020 Mar 27. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Not Available
- Specific Function
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23511.38 Da
References
- Johne A, Scheible H, Becker A, van Lier JJ, Wolna P, Meyring M: Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers. Invest New Drugs. 2020 Oct;38(5):1507-1519. doi: 10.1007/s10637-020-00926-1. Epub 2020 Mar 27. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- Wu ZX, Teng QX, Cai CY, Wang JQ, Lei ZN, Yang Y, Fan YF, Zhang JY, Li J, Chen ZS: Tepotinib reverses ABCB1-mediated multidrug resistance in cancer cells. Biochem Pharmacol. 2019 Aug;166:120-127. doi: 10.1016/j.bcp.2019.05.015. Epub 2019 May 9. [Article]
- FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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: Tepmetko (tepotinib) tablets for oral use [Link]
Drug created at May 20, 2019 14:52 / Updated at May 23, 2022 17:31