You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
Nameado-trastuzumab emtansine
Accession NumberDB05773
TypeSmall Molecule
GroupsApproved
Description

Ado-trastuzumab emtansine, formerly called Trastuzumab-DM1 (T-DM1) as an investigational drug, 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. Ado-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 ado-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.

Structure
Thumb
Synonyms
SynonymLanguageCode
trastuzumab emtansineNot AvailableNot Available
Trastuzumab-DM1Not AvailableNot Available
trastuzumab-MCC-DM1Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
KadcylaGenentech
Brand mixturesNot Available
Categories
CAS number1018448-65-1
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Mass SpecNot Available
Taxonomy
KingdomNot Available
SuperclassNot Available
ClassNot Available
SubclassNot Available
Direct parentNot Available
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationUsed 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.
PharmacodynamicsAdo-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 ado-trastuzumab emtansine are cell cycle arrest and cell death by apoptosis.
Mechanism of actionAdo-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. Ado-trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade ado-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 ado-trastuzumab emtansine.
AbsorptionThe absorption/ bioavailability should be close to 100% since ado-trastuzumab emtansine is administered IV.
Volume of distribution

The volume of distribution of ado-trastuzumab emtansine is about 3.13 L.

Protein bindingDM1 has a plasma protein binding value of 93%.
Metabolism

Ado-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 eliminationThe route of elimination has not yet been fully elucidated.
Half lifeAdo-trastuzumab emtansine has a long half life of about 4 days.
Clearance

After IV infusion, ado-trastuzumab emtansine has a clearance of 0.68 L/day.

ToxicityThe FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption Not Available Not Available
Blood Brain Barrier Not Available Not Available
Caco-2 permeable Not Available Not Available
P-glycoprotein substrate Not Available Not Available
P-glycoprotein inhibitor I Not Available Not Available
P-glycoprotein inhibitor II Not Available Not Available
Renal organic cation transporter Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 1A2 substrate Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 2C19 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 inhibitory promiscuity Not Available Not Available
Ames test Not Available Not Available
Carcinogenicity Not Available Not Available
Biodegradation Not Available Not Available
Rat acute toxicity Not Available Not applicable
hERG inhibition (predictor I) Not Available Not Available
hERG inhibition (predictor II) Not Available Not Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous100MG
Injection, powder, lyophilized, for solutionIntravenous160MG
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted PropertiesNot Available
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. FDA label.
  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. Pubmed
External Links
ResourceLink
KEGG DrugD09980
RxListhttp://www.rxlist.com/kadcyla-drug.htm
Drugs.comhttp://www.drugs.com/mtm/ado-trastuzumab-emtansine.html
WikipediaTrastuzumab_emtansine
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(428 KB)
MSDSshow(381 KB)
Interactions
Drug Interactions
Drug
BelimumabAvoid combination due to the increased risk of belimumab associated side effects.
ClozapineAvoid combination due to the increased potential for agranulocytosis.
NatalizumabAvoid combination due to the increased risk of infection.
PhenytoinAvoid combination with phenytoin and other strong CYP3A4 inducers due to the likely increase in metabolism of ado-trastuzumab emtansine to its active component, DM1.
PimecrolimusAvoid combination due to the increase in immunosuppressant side effects.
TacrolimusAvoid combination due to the increase in immunosuppressant side effects.
TofacitinibAvoid combination with tofacitinib and other potent immunosuppressants due to the likely enhancement of immunosuppression.
Food InteractionsNot Available

Targets

1. Receptor tyrosine-protein kinase erbB-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antibody

Components

Name UniProt ID Details
Receptor tyrosine-protein kinase erbB-2 P04626 Details

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. Pubmed
  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. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

From FDA label.


2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

From FDA label.


Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

From FDA label.


Comments
comments powered by Disqus
Drug created on November 18, 2007 11:27 / Updated on September 16, 2013 17:43