Identification
- Summary
Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing breast cancer.
- Brand Names
- Kadcyla
- Generic Name
- Trastuzumab emtansine
- DrugBank Accession Number
- DB05773
- Background
Trastuzumab emtansine, formerly called Trastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody drug conjugate (ADC) comprised of Genentech's trastuzumab antibody linked to ImmunoGen's cell-killing agent, DM1. T-DM1 combines two strategies-- anti-HER2 activity and targeted intracellular delivery of the potent anti-microtubule agent, DM1 (a maytansine derivative)--to produce cell cycle arrest and apoptosis. Trastuzumab emtansine is marketed under the brand name Kadcyla and is indicated for use in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. The FDA label has two precautions. First that trastuzumab emtansine and trastuzumab cannot be interchanged. Second that there is a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Ado-trastuzumab
- Ado-trastuzumab emtansine
- T-DM1
- Trastuzumab emtansine
- Trastuzumab-DM1
- Trastuzumab-MCC-DM1
- External IDs
- PRO-132365
- PRO132365
- RG-3502
Pharmacology
- Indication
Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment.
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 Adjunct therapy in treatment of Her2-positive early stage breast cancer •••••••••••• •••••••• •••••••••••• ••••••••••••• •••••••••• ••••••• •••• •••••••••••• •••••••• •••••••• •••••• •••••• Treatment of Her2-positive, metastatic breast cancer •••••••••••• •••• •••••••• •• ••••••••••• ••••••• •• •• •••••• • ••••••• •••••••• •••••••••••• ••••••••••••• •••••••••• ••••••• •••• ••••••••••• Treatment of Her2-positive, metastatic breast cancer •••••••••••• •••••••••• ••••••• •••• •••••••••••• •••••••• •••••••••••• •••••••••••• - Contraindications & Blackbox Warnings
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Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis.
- Mechanism of action
Trastuzumab emtansine is a HER2 antibody-drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis.
Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine.
Target Actions Organism AReceptor tyrosine-protein kinase erbB-2 antibodyHumans - Absorption
The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV.
- Volume of distribution
The volume of distribution of trastuzumab emtansine is about 3.13 L.
- Protein binding
DM1 has a plasma protein binding value of 93%.
- Metabolism
Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes.
- Route of elimination
The route of elimination has not yet been fully elucidated.
- Half-life
Trastuzumab emtansine has a long half life of about 4 days.
- Clearance
After IV infusion, trastuzumab emtansine has a clearance of 0.68 L/day.
- Adverse Effects
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The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Trastuzumab emtansine can be increased when it is combined with Abametapir. Abatacept The metabolism of Trastuzumab emtansine can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Trastuzumab emtansine. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Trastuzumab emtansine. Abrocitinib The serum concentration of Trastuzumab emtansine can be increased when it is combined with Abrocitinib. - Food Interactions
- Avoid grapefruit products. Trastuzumab emtansine undergoes metabolism through CYP3A4 therefore coadministration with grapefruit, a CYP3A4 inhibitor, may increase serum levels of trastuzumab emtansine.
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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Kadcyla Injection, powder, for solution 100 mg Intravenous Roche Registration Gmb H 2020-12-23 Not applicable EU 
Kadcyla Injection, powder, lyophilized, for solution 20 mg/1mL Intravenous Genentech, Inc. 2013-02-22 Not applicable US 
Kadcyla Powder, for solution 160 mg / vial Intravenous Hoffmann La Roche 2018-10-24 Not applicable Canada 
Kadcyla Injection, powder, lyophilized, for solution 20 mg/1mL Intravenous Genentech, Inc. 2013-02-22 Not applicable US Kadcyla Injection, powder, for solution 160 mg Intravenous Roche Registration Gmb H 2020-12-23 Not applicable EU
Categories
- ATC Codes
- L01FD03 — Trastuzumab emtansine
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antibody-drug Conjugates
- Antimitotic Agents
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- Cancer immunotherapy
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Globulins
- Hepatotoxic Agents
- HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors
- HER2 Receptor Antagonists
- HER2-targeted Antibodies
- Immunoconjugates
- Immunoglobulins
- Immunologic Factors
- Immunoproteins
- Immunosuppressive Agents
- Immunotherapy
- Immunotoxins
- Lactams, Macrocyclic
- Lactones
- Maytansine
- Microtubule Inhibitors
- Mitosis Modulators
- MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- Noxae
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Proteins
- Serum Globulins
- Toxic Actions
- Trastuzumab
- Tubulin Modulators
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- SE2KH7T06F
- CAS number
- 1018448-65-1
References
- General References
- Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776. [Article]
- External Links
- KEGG Drug
- D09980
- PubChem Substance
- 347910224
- 1371041
- ChEMBL
- CHEMBL1743082
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Trastuzumab_emtansine
- FDA label
- Download (428 KB)
- MSDS
- Download (381 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Basic Science Breast Cancer, HER2 Positive Breast Cancer, Metastatic Breast Cancer, Locally Advanced Breast Cancer 1 3 Active Not Recruiting Treatment Breast Cancer 2 3 Active Not Recruiting Treatment HER2-Positive Primary Breast Cancer / Residual Invasive Breast Cancer 1 3 Active Not Recruiting Treatment Inflammatory Breast Cancer (IBC) / Locally Advanced Breast Cancer (LABC) / Stage I Breast Cancer 1 3 Active Not Recruiting Treatment Metastatic Breast Cancer 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous; Parenteral 100 MG Injection, powder, for solution Intravenous; Parenteral 160 MG Injection, powder, lyophilized, for solution Intravenous 20 mg/1mL Powder, for solution Intravenous 100 mg / vial Powder, for solution Intravenous 160 mg / vial Solution Intravenous 106.000 mg Injection, solution Intravenous 100 mg Injection, solution Intravenous 160 mg Injection, powder, for solution Intravenous 20 mg/mL Injection, powder, for solution Intravenous 100 mg Injection, powder, for solution Intravenous 160 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antibody
- General Function
- Transmembrane signaling receptor activity
- Specific Function
- Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
- Gene Name
- ERBB2
- Uniprot ID
- P04626
- Uniprot Name
- Receptor tyrosine-protein kinase erbB-2
- Molecular Weight
- 137909.27 Da
References
- Barginear MF, John V, Budman DR: Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med. 2013 Jan 22;18:1473-9. doi: 10.2119/molmed.2012.00302. [Article]
- Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- 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
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Authors unspecified: Trastuzumab emtansine. An inadequately assessed combination of two cytotoxic drugs. Prescrire Int. 2014 Dec;23(155):289. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- The emtansine component of the drug-antibody conjugate is the P-glycoprotein substrate.
- 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
Drug created at November 18, 2007 18:27 / Updated at June 03, 2022 07:24