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
trastuzumab emtansine
Trastuzumab-DM1
trastuzumab-MCC-DM1
External Identifiers
  • RG-3502
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kadcylainjection, powder, lyophilized, for solution20 mg/mLintravenousGenentech, Inc.2013-02-222016-04-05Us
Kadcylapowder for solution20 mgintravenousHoffmann La Roche Limited2013-10-09Not applicableCanada
Kadcylainjection, powder, lyophilized, for solution20 mg/mLintravenousGenentech, Inc.2013-02-222016-04-05Us
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIISE2KH7T06F
CAS number1018448-65-1
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Taxonomy
ClassificationNot classified
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.
Related Articles
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
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous20 mg/mL
Powder for solutionintravenous20 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted PropertiesNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
References
Synthesis ReferenceNot Available
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. [PubMed:19010901 ]
External Links
ATC CodesL01XC14
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (428 KB)
MSDSDownload (381 KB)
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Atazanavir.
BelimumabThe risk or severity of adverse effects can be increased when ado-trastuzumab emtansine is combined with Belimumab.
BoceprevirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Boceprevir.
CeritinibThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Ceritinib.
ClarithromycinThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Clarithromycin.
ClozapineThe risk or severity of adverse effects can be increased when ado-trastuzumab emtansine is combined with Clozapine.
CobicistatThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Cobicistat.
ConivaptanThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Conivaptan.
DarunavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Darunavir.
DasatinibThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Dasatinib.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with ado-trastuzumab emtansine.
FluconazoleThe metabolism of ado-trastuzumab emtansine can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Indinavir.
ItraconazoleThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Itraconazole.
IvacaftorThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Ketoconazole.
LeflunomideThe risk or severity of adverse effects can be increased when ado-trastuzumab emtansine is combined with Leflunomide.
LuliconazoleThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Luliconazole.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with ado-trastuzumab emtansine.
MifepristoneThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Mifepristone.
NatalizumabThe risk or severity of adverse effects can be increased when ado-trastuzumab emtansine is combined with Natalizumab.
NefazodoneThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Nefazodone.
NelfinavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Nelfinavir.
NetupitantThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Palbociclib.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with ado-trastuzumab emtansine.
PosaconazoleThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Posaconazole.
RitonavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Ritonavir.
RoflumilastRoflumilast may increase the immunosuppressive activities of ado-trastuzumab emtansine.
SaquinavirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Saquinavir.
SimeprevirThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with ado-trastuzumab emtansine.
StiripentolThe serum concentration of ado-trastuzumab emtansine can be increased when it is combined with Stiripentol.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with ado-trastuzumab emtansine.
TelaprevirThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Telaprevir.
TelithromycinThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Telithromycin.
Tofacitinibado-trastuzumab emtansine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of ado-Trastuzumab emtansine.
VoriconazoleThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Voriconazole.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
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, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-...
Gene Name:
ERBB2
Uniprot ID:
P04626
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. [PubMed:23196784 ]
  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:19010901 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References

From FDA label.

Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References

From FDA label.

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
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
Molecular Weight:
141477.255 Da
References

From FDA label.

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