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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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.

TargetActionsOrganism
AReceptor tyrosine-protein kinase erbB-2
antibody
Humans
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
Adverseeffects
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Toxicity

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
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
AbametapirThe serum concentration of Trastuzumab emtansine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Trastuzumab emtansine can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Trastuzumab emtansine.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Trastuzumab emtansine.
AbirateroneThe metabolism of Trastuzumab emtansine can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Trastuzumab emtansine can be decreased when combined with Acalabrutinib.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Trastuzumab emtansine.
AcetaminophenThe metabolism of Trastuzumab emtansine can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Trastuzumab emtansine can be decreased when combined with Acetazolamide.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Trastuzumab emtansine.
Interactions
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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

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KadcylaInjection, powder, lyophilized, for solution20 mg/1mLIntravenousGenentech, Inc.2013-02-22Not applicableUS flag
KadcylaInjection, powder, for solution100 mgIntravenousRoche Registration Gmb H2020-12-23Not applicableEU flag
KadcylaPowder, for solution160 mg / vialIntravenousHoffmann La Roche2018-10-24Not applicableCanada flag
KadcylaInjection, powder, lyophilized, for solution20 mg/1mLIntravenousGenentech, Inc.2013-02-22Not applicableUS flag
KadcylaPowder, for solution100 mg / vialIntravenousHoffmann La Roche2013-10-09Not applicableCanada flag
KadcylaInjection, powder, for solution160 mgIntravenousRoche Registration Gmb H2020-12-23Not applicableEU flag

Categories

ATC Codes
L01XC14 — Trastuzumab emtansine
Drug Categories
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
  1. 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]
KEGG Drug
D09980
PubChem Substance
347910224
RxNav
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
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceBreast Cancer, HER2 Positive Breast Cancer, Metastatic Breast Cancer, Locally Advanced Breast Cancer1
3Active Not RecruitingTreatmentBreast Cancer4
3CompletedTreatmentBreast Cancer5
3CompletedTreatmentNeoplasms, Breast1
3RecruitingTreatmentAnatomic Stage IA Breast Cancer AJCC v8 / Anatomic Stage II Breast Cancer AJCC v8 / Anatomic Stage IIA Breast Cancer AJCC v8 / Anatomic Stage IIB Breast Cancer AJCC v8 / Anatomic Stage III Breast Cancer AJCC v8 / Anatomic Stage IIIA Breast Cancer AJCC v8 / Anatomic Stage IIIB Breast Cancer AJCC v8 / Anatomic Stage IIIC Breast Cancer AJCC v8 / HER2 Positive Carcinoma of Breast / Invasive Breast Carcinoma / Multifocal Breast Carcinoma / Prognostic Stage 1 Breast Cancer AJCC v8 / Prognostic Stage 2 Breast Cancer AJCC v8 / Prognostic Stage IA Breast Cancer AJCC v8 / Prognostic Stage IB Breast Cancer AJCC v8 / Prognostic Stage IIA Breast Cancer AJCC v8 / Prognostic Stage IIB Breast Cancer AJCC v8 / Prognostic Stage III Breast Cancer AJCC v8 / Prognostic Stage IIIA Breast Cancer AJCC v8 / Prognostic Stage IIIB Breast Cancer AJCC v8 / Prognostic Stage IIIC Breast Cancer AJCC v8 / Synchronous Bilateral Breast Carcinoma1
3RecruitingTreatmentBreast Cancer1
3RecruitingTreatmentHER2-Positive Primary Breast Cancer / Residual Invasive Breast Cancer1
3RecruitingTreatmentHER2/Neu-positive Breast Cancer1
3RecruitingTreatmentMetastatic Breast Cancer1
3TerminatedTreatmentMetastatic Breast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous; Parenteral100 MG
Injection, powder, for solutionIntravenous; Parenteral160 MG
Injection, powder, lyophilized, for solutionIntravenous20 mg/1mL
Powder, for solutionIntravenous100 mg / vial
Powder, for solutionIntravenous160 mg / vial
Injection, solutionIntravenous
Injection, powder, for solutionIntravenous
Injection, powder, for solutionIntravenous100 mg
Injection, powder, for solutionIntravenous160 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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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
  1. 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]
  2. 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]
  3. 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
  1. 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 October 26, 2021 21:40