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.
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|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.|
|Pharmacodynamics||Ado-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 action||Ado-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.|
|Absorption||The 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 binding||DM1 has a plasma protein binding value of 93%.|
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 elimination||The route of elimination has not yet been fully elucidated.|
|Half life||Ado-trastuzumab emtansine has a long half life of about 4 days.|
After IV infusion, ado-trastuzumab emtansine has a clearance of 0.68 L/day.
|Toxicity||The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.|
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|FDA label||Download (428 KB)|
|MSDS||Download (381 KB)|
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Pharmacological action: yes
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- 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
- 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
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Pharmacological action: unknown
|Cytochrome P450 3A4||P08684||Details|
From FDA label.