Tepotinib

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tepotinib (DB15133)

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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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Associated Conditions

• Metastatic Non-Small Cell Lung Cancer

Contraindications & Blackbox Warnings

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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	inhibitor	Humans
UNischarin	inhibitor	Humans
UMelatonin receptor type 1B	inhibitor	Humans

Absorption

The absolute bioavailability of tepotinib following oral administration is approximately 72%.^7,3 At the recommended dosage of 450mg once daily, the median T_max is 8 hours and the mean steady-state C_max and AUC_0-24h 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 C_max 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

Hover over products below to view reaction partners

• Tepotinib
  • Tepotinib M506 metabolite
  • Tepotinib M478 metabolite
  • Tepotinib M508 metabolite

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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Toxicity

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abaloparatide	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.
Abiraterone	The metabolism of Tepotinib can be decreased when combined with Abiraterone.
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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Food Interactions

• Take with food. Co-administration with a meal improves the absorption of tepotinib.

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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	Oral	Emd Serono, A Division Of Emd Inc., Canada	Not applicable	Not applicable
Tepmetko	Tablet	225 mg/1	Oral	EMD Serono, Inc.	2021-02-03	Not applicable

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

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. Markham A: Tepotinib: First Approval. Drugs. 2020 Jun;80(8):829-833. doi: 10.1007/s40265-020-01317-9. [Article]
7. FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]
8. CaymanChem: Tepotinib MSDS [Link]
9. 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

RxNav

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	Recruiting	Treatment	MET Amplification / MET exon 14 skipping mutation / Tumors, Solid	1
2	Recruiting	Treatment	Neoplasms, Colorectal	1
2	Recruiting	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	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	Tumors, Solid	1
1, 2	Completed	Treatment	Hepatocellular Carcinoma	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	225 mg
Tablet	Oral	225 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8658643	No	2014-02-25	2028-07-04
US8927540	No	2015-01-06	2028-07-21
US9403799	No	2016-08-02	2028-07-04
US8580781	No	2013-11-12	2030-03-19
US8921357	No	2014-12-30	2028-05-30
US9062029	No	2015-06-23	2028-07-04
US8329692	No	2012-12-11	2029-10-30
US9284300	No	2016-03-15	2028-04-29

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

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Details1. Hepatocyte growth factor receptor

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: Tepmetko (tepotinib) tablets for oral use [Link]

Details2. Nischarin

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

1. FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]

Details3. Melatonin receptor type 1B

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

1. FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]

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Drug created at May 20, 2019 14:52 / Updated at October 25, 2021 00:51