Introduction
Trastuzumab emtansine (T-DM1) is a targeted antibody-drug conjugate (ADC) that combines the HER2-targeting monoclonal antibody trastuzumab with the potent microtubule inhibitor DM1 (a maytansine derivative). It selectively delivers the cytotoxic agent into HER2-positive cancer cells, where it disrupts microtubules, causing cell cycle arrest and apoptosis while retaining the anti-HER2 activity of trastuzumab. T-DM1 is primarily used to treat HER2-positive metastatic breast cancer, particularly in patients previously treated with trastuzumab and/or a taxane. It carries important safety warnings for hepatotoxicity, embryo-fetal toxicity, and cardiotoxicity, and should not be used interchangeably with trastuzumab.
Uses
Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing breast cancer.
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.
Associated Conditions
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.
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%.
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.
Toxicity
The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
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.
Dosage
First Infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusionrelated reactions
Subsequent Infusions: Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after infusion.