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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
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 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
Adverseeffects
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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.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Tepotinib.
AbametapirThe serum concentration of Tepotinib can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Tepotinib.
AbirateroneThe metabolism of Tepotinib can be decreased when combined with Abiraterone.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Tepotinib.
AfatinibThe serum concentration of Tepotinib can be increased when it is combined with Afatinib.
AllopurinolTepotinib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Tepotinib.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Tepotinib.
AmiodaroneThe serum concentration of Tepotinib can be increased when it is combined with Amiodarone.
Interactions
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Food Interactions
  • Take with food. Co-administration with a meal improves the absorption of tepotinib.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Tepotinib hydrochlorideVY5YX2TQ1F1946826-82-9KZVOMLRKFJUTLK-UHFFFAOYSA-N
International/Other Brands
Tepmetko (EMD Serono)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TepmetkoTablet225 mgOralEmd Serono, A Division Of Emd Inc., CanadaNot applicableNot applicableCanada flag
TepmetkoTablet225 mg/1OralEMD Serono, Inc.2021-02-03Not applicableUS flag

Categories

Drug Categories
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]
ChemSpider
28637823
BindingDB
50065457
RxNav
2477103
ChEMBL
CHEMBL3402762
ZINC
ZINC000043202335
PDBe Ligand
3E8
Wikipedia
C-Met_inhibitor
PDB Entries
4r1v

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentAdvanced (Stage IIIB/IV) Non-small Cell Lung Cancer (NSCLC) With MET Exon 14 (METex14) Skipping Alterations or MET Amplification1
2RecruitingTreatmentMET Amplification / MET exon 14 skipping mutation / Tumors, Solid1
2RecruitingTreatmentNeoplasms, Colorectal1
2RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
1CompletedOtherHealthy Subjects (HS)5
1CompletedOtherHepatic Impairment1
1CompletedTreatmentHealthy Subjects (HS)1
1CompletedTreatmentPatients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available1
1CompletedTreatmentTumors, Solid1
1, 2CompletedTreatmentHepatocellular Carcinoma2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral225 mg
TabletOral225 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8658643No2014-02-252028-07-04US flag
US8927540No2015-01-062028-07-21US flag
US9403799No2016-08-022028-07-04US flag
US8580781No2013-11-122030-03-19US flag
US8921357No2014-12-302028-05-30US flag
US9062029No2015-06-232028-07-04US flag
US8329692No2012-12-112029-10-30US flag
US9284300No2016-03-152028-04-29US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa9.5FDA Label
Predicted Properties
PropertyValueSource
logP4ChemAxon
pKa (Strongest Basic)9.13ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area94.71 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity154.74 m3·mol-1ChemAxon
Polarizability54.7 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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]
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]
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]

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: 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
  1. 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
  1. 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
  1. 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
Substrate
Inhibitor
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. 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]
  2. 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
  1. FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use [Link]

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