Trastuzumab emtansine
Trastuzumab emtansine Uses, Dosage, Side Effects, Food Interaction and all others data.
Trastuzumab emtansine is a HER2-targeted antibody-drug conjugate which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumor cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1). Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1.
Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, Trastuzumab emtansine, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.
DM1, the cytotoxic drug component of Trastuzumab emtansine, binds to tubulin. By inhibiting tubulin polymerization, both DM1 and Trastuzumab emtansine cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20–200 times more potent than taxanes and vinca alkaloids.
The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.
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.
| Trade Name | Trastuzumab emtansine |
| Generic | Trastuzumab Emtansine |
| Trastuzumab Emtansine Other Names | Ado-trastuzumab, Ado-trastuzumab emtansine, T-DM1, Trastuzumab emtansine, Trastuzumab-DM1, Trastuzumab-MCC-DM1 |
| Type | |
| Protein binding | DM1 has a plasma protein binding value of 93%. |
| Groups | Approved, Investigational |
| Therapeutic Class | Anti neoplastic preparations |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Metastatic Breast Cancer (MBC): Trastuzumab emtansine, as a single agent, is used for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane.
Trastuzumab emtansine is also used to associated treatment for these conditions: Refractory, metastatic Non small cell lung cancer
How Trastuzumab emtansine works
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.
Dosage
Trastuzumab emtansine dosage
Recommended Doses And Schedules: The recommended dose of Trastuzumab emtansine is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.Do not administer Trastuzumab emtansine at doses greater than 3.6 mg/kg.Do not substitute Trastuzumab emtansine for or with trastuzumab. Closely monitor the infusion site for possible subcutaneous infiltration during drug administration
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.
Toxicity
The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
Precaution
Patients treated with Trastuzumab emtansine must have confirmed HER2-positive tumor status as assessed by either HER2 protein overexpression or gene amplification.
Interaction
No formal drug-drug interaction studies with trastuzumab emtansine in humans have been conducted. In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and, to a lesser extent, by CYP3A5. DM1 does not induce or inhibit P450-mediated metabolism in vitro. Caution should be taken when trastuzumab emtansine is co-administered with potent CYP3A inhibitors.
Food Interaction
- Avoid grapefruit products. Trastuzumab emtansine undergoes metabolism through CYP3A4 therefore coadministration with grapefruit, a CYP3A4 inhibitor, may increase serum levels of trastuzumab emtansine.
Volume of Distribution
The volume of distribution of trastuzumab emtansine is about 3.13 L.
Elimination Route
The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV.
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.
Elimination Route
The route of elimination has not yet been fully elucidated.
Pregnancy & Breastfeeding use
Pregnancy: There are no clinical studies of trastuzumab emtansine in pregnant women. No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm or death when administered to a pregnant woman. In the postmarketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic drug component of trastuzumab emtansine, is expected to be teratogenic and potentially embryotoxic.
Administration of trastuzumab emtansine to pregnant women is not recommended. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.
Nursing Mothers: It is not known whether trastuzumab emtansine is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Kadcyla, women should discontinue nursing prior to initiating treatment with trastuzumab emtansine. Women may begin nursing 7 months after concluding treatment.
Contraindication
Trastuzumab emtansine is contraindicated in patients with a known hypersensitivity to Trastuzumab emtansine or any of its excipients
Special Warning
Pediatric Use: The safety and efficacy of Trastuzumab emtansine in children below 18 years of age have not been established.
Geriatric Use: There are insufficient data to establish the safety and efficacy of Trastuzumab emtansine in patients 75 years of age or older.
Storage Condition
Store vials at 2°C-8°C.
Innovators Monograph
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FAQ
What is Trastuzumab emtansine used for?
Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing breast cancer.
How does Trastuzumab emtansine work in the body?
Trastuzumab emtansine attaches to the HER2 proteins and can stop them growing. It also helps the body's immune system to destroy cancer cells. When the Trastuzumab emtansine attaches to the proteins, it delivers emtansine directly into the breast cancer cells.
What are the common side effects of Trastuzumab emtansine?
The common side effects of Trastuzumab emtansine are include:
- constipation
- diarrhea
- upset stomach
- sores in the mouth and throat
- dry mouth
- changes in ability to taste
- joint or muscle pain
- headache
- dry, red, or teary eyes
- blurry vision
- trouble falling asleep or staying asleep
Is Trastuzumab emtansine safe during pregnancy?
Trastuzumab emtansine should not be administered during pregnancy if at all possible. Unintentional exposure during the first trimester is probably safe for the fetus making continuation of pregnancy an option.
Is Trastuzumab emtansine safe during breastfeeding?
Based on its mechanism of action, the cytotoxic component of this drug may cause serious adverse reactions in breastfed infants.
Can I drink alcohol with Trastuzumab emtansine?
The drinking of alcohol does not appear to affect the safety or usefulness of Trastuzumab emtansine. children, discuss this with your doctor before being treated with Trastuzumab emtansine.
Can Trastuzumab emtansine causes Lung problems?
Trastuzumab emtansine may cause inflammation of the lungs, which can be life-threatening. Symptoms include trouble breathing, cough, tiredness, and fluid in the lungs.
Can Trastuzumab emtansine causes Liver problems?
Trastuzumab emtansine may cause severe liver problems, including liver failure.
Can Trastuzumab emtansine causes hair loss?
Hair loss usually starts after your first or second treatment. It is almost always temporary, and your hair will usually grow back after treatment finishes.
How do I give Trastuzumab emtansine?
Trastuzumab emtansine is given as an intravenous infusion in your doctor's office, at a hospital, or at an infusion center.
How often is Trastuzumab emtansine given?
The recommended dose of Trastuzumab emtansine given as an intravenous infusion 26 every 3 weeks until disease progression or unacceptable toxicity.
Can Trastuzumab emtansine affect eyesight?
eye problems such as dry eyes, watery eyes, blurred vision, redness of the eye or an infection. high blood pressure.
What happens if I miss a dose?
Call your doctor for instructions if you miss an appointment for your ado-Trastuzumab emtansine injection.
What happens if I overdose?
Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.
