ado-trastuzumab emtansine

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action:  

ado-trastuzumab emtansine is a combination of two components: trastuzumab and DM1. trastuzumab is a monoclonal antibody specifically targeting the HER2 (human epidermal growth factor receptor 2) protein, which is overexpressed in HER2-positive breast cancer. trastuzumab binds to the HER2 protein, inhibiting its signaling pathway and interfering with the growth and survival of cancer cells. 

DM1, on the other hand, is a cytotoxic agent, also known as a microtubule inhibitor. It is a derivative of maytansine and is highly potent in disrupting microtubule function, resulting in cell cycle arrest and apoptosis (programmed cell death). DM1 is attached to trastuzumab through a stable linker, allowing targeted delivery of the cytotoxic agent to HER2-positive cancer cells. 

Once ado-trastuzumab emtansine binds to HER2-positive cancer cells, the cells internalize it through receptor-mediated endocytosis. The DM1 component is released within the cancer cells, leading to cytotoxic effects on the cancer cells. 

Spectrum of Activity:  

ado-trastuzumab emtansine is primarily indicated for the treatment of HER2-positive breast cancer. This includes early-stage and metastatic breast cancer cases where the HER2 protein is overexpressed. HER2-positive breast cancer is characterized by aggressive tumor behavior and is associated with a poorer prognosis than HER2-negative breast cancer. 

The targeted nature of ado-trastuzumab emtansine allows for selective delivery of the cytotoxic agent to HER2-positive cancer cells, minimizing damage to normal cells and potentially improving the therapeutic index. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

(All Grades for MBC) 

Fatigue (36%) 

Hemorrhage (32%) 

AST/ALT increased (29%) 

Headache (28%) 

Epistaxis (23%) 

Vomiting (19%) 

Pyrexia (19%) 

Asthenia (18%) 

Nausea (40%) 

Musculoskeletal pain (36%) 

Thrombocytopenia (31%) 

Constipation (27%) 

Diarrhea (24%) 

Peripheral neuropathy (21%) 

Abdominal pain (19%) 

Arthralgia (19%) 

>10% (All Grades for EBC) 

Nausea (42%) 

Musculoskeletal pain (30%) 

Hemorrhage (29%) 

Headache (28%) 

Arthralgia (26%) 

Constipation (17%) 

Stomatitis (15%) 

Fatigue (50%) 

AST/ALT increased (32%) 

Thrombocytopenia (29%) 

Peripheral neuropathy (28%) 

Epistaxis (22%) 

Myalgia (15%) 

>10% (MBC [Grade 3 or 4]) 

Thrombocytopenia (15%) 

1-10% (All Grades) 

MBC 

Dizziness (10%) 

Hypokalemia (10%)  

EBC 

Pyrexia (10%) 

Urinary tract infection (10%) 

Anemia (10%) 

Dizziness (10%)  

1-10% (Grade 3 or 4) 

MBC 

Anemia (4.1%) 

Fatigue (2.5%) 

Musculoskeletal pain (1.8%) 

Hemorrhage (1.8%) 

AST/ALT increased (8%) 

Hypokalemia (2.7%) 

Peripheral neuropathy (2.2%) 

Diarrhea (1.6%) 

EBC 

Peripheral neuropathy (1.6%) 

AST/ALT increased (1.5%) 

Thrombocytopenia (6%)  

<1% (Grade 3 or 4) 

Headache (0.8%) 

Arthralgia/myalgia (0.6%) 

Constipation (0.4%) 

Nausea/vomiting (0.8%) 

Dyspnea (0.8%) 

Nausea (0.5%) 

Asthenia (0.4%) 

Black Box Warning

Black box warning: 

Hepatotoxicity: 

• Severe hepatotoxicity, including liver failure and death, has been reported. 
• Serum transaminases (liver enzymes) and bilirubin levels should be monitored before starting treatment and each dose. 
• The dosage may need to be reduced or discontinued if transaminases or bilirubin levels are elevated. 

Cardiac toxicity: 

• T-DM1 may decrease the left ventricular ejection fraction (LVEF), which measures heart function. 
• LVEF should be evaluated in all patients before and during treatment. 
• Treatment should be withheld for a clinically significant decrease in LVEF. 

Embryofetal toxicity: 

• T-DM1 can cause embryofetal death or congenital disabilities. 
• Postmarketing reports have associated it with conditions such as oligohydramnios (reduced amniotic fluid), fatal pulmonary hypoplasia (underdeveloped lungs), skeletal abnormalities, and neonatal death. 
• Patients should be informed of the risks and the importance of effective contraception. 
• Pregnancy status should be verified before initiating treatment. 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

None 

Caution: 

• Hepatic impairment: T-DM1 should be used cautiously in patients with pre-existing hepatic impairment. Close monitoring of liver function, including serum transaminases (liver enzymes) and bilirubin levels, is recommended in such cases. 
• Cardiac dysfunction: T-DM1 may lead to decreased left ventricular ejection fraction (LVEF) and cardiac toxicity. Patients with pre-existing cardiac conditions or a history of cardiac dysfunction should be closely monitored. LVEF assessments should be performed before and during treatment. 
• Pulmonary toxicity: Cases of interstitial lung disease (ILD) and pneumonitis have been reported with T-DM1. Patients experiencing new or worsening pulmonary symptoms should be evaluated promptly, and treatment may need to be interrupted or discontinued if ILD or pneumonitis is confirmed. 
• Thrombocytopenia and bleeding: T-DM1 may cause a decrease in platelet count, leading to an increased risk of bleeding. Monitoring of platelet levels is essential, and caution should be exercised in patients with a history of bleeding disorders. 
• Infusion reactions: Infusion-related reactions, including fever, chills, flushing, and breathing difficulties, have been reported with T-DM1. Healthcare providers should closely monitor patients during infusion and be prepared to manage such reactions appropriately. 
• Embryofetal toxicity and contraception: T-DM1 can cause harm to the developing fetus. Effective contraception should be used during treatment with T-DM1, and pregnancy status should be verified before initiation. 
• Pediatric use: The safety and efficacy of T-DM1 in pediatric patients have not been established, so caution should be exercised when considering its use in this population. 

Pregnancy / Lactation

Pregnancy consideration: It is generally not recommended due to the potential risks it may pose to the developing fetus 

Pregnancy category: D 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

T-DM1 exerts its antitumor activity through a dual mechanism. The trastuzumab component targets and binds specifically to the HER2 (human epidermal growth factor receptor 2) protein overexpressed on the surface of HER2-positive cancer cells. This binding inhibits the HER2 signaling pathway, which plays a role in cell growth and survival. The DM1 component, a microtubule-disrupting agent, is released upon internalization of the T-DM1 complex into the cancer cells. DM1 inhibits microtubule assembly, leading to cell cycle arrest and cell death. 

Pharmacodynamics: 

The critical aspects of the pharmacodynamics of T-DM1: 

• HER2 Receptor Inhibition: trastuzumab, the anti-HER2 antibody component of T-DM1, binds to the HER2 receptors on the surface of HER2-positive cancer cells. This binding inhibits the downstream signaling pathways that promote cell growth and survival. By targeting and blocking HER2 receptors, T-DM1 interferes with the HER2-driven signaling cascades. 
• Cell Cycle Arrest: The DM1 component of T-DM1, a cytotoxic agent, exerts its effect inside the cancer cells. Upon internalization of the T-DM1 complex into the HER2-positive cancer cells, DM1 is released. DM1 inhibits microtubule assembly, leading to cell cycle arrest in the G2/M phase. This disruption of microtubule dynamics prevents proper cell division and ultimately results in cell death. 
• Antibody-Dependent Cellular Cytotoxicity (ADCC): Trastuzumab, as an antibody component, can also engage the immune system to facilitate the destruction of cancer cells. Trastuzumab can bind to the Fc receptors on immune cells (such as natural killer cells), leading to antibody-dependent cellular cytotoxicity. This immune response contributes to the antitumor activity of T-DM1. 
• Pharmacodynamic Biomarkers: Various pharmacodynamic biomarkers can be assessed to monitor the response to T-DM1. These include changes in HER2 expression levels, downstream signaling pathway activity, cell cycle markers, and cell death or proliferation indicators. Monitoring these biomarkers can provide insight into the pharmacological effects of T-DM1 on HER2-positive cancer cells. 

Pharmacokinetics: 

Absorption 

T-DM1 is administered intravenously, which allows for immediate and complete bioavailability. 

Distribution 

Once in the bloodstream, T-DM1 distributes systemically. trastuzumab, the antibody component of T-DM1, is expected to distribute similarly to other monoclonal antibodies. DM1, the cytotoxic component, is also distributed in the body but may have a different distribution profile due to its smaller molecular weight and hydrophobic nature. 

Metabolism 

trastuzumab undergoes catabolism by proteolytic enzymes. DM1, on the other hand, is primarily metabolized by hepatic enzymes, particularly cytochrome P450 (CYP) enzymes. CYP3A4 and CYP3A5 are involved in the metabolism of DM1. 

Elimination and Excretion 

The elimination of T-DM1 involves several routes. Proteolytic degradation of trastuzumab and metabolism of DM1 in the liver contribute to its clearance. The primary route of excretion is through feces, with a smaller portion eliminated via urine. 

Adminstartion

Administration: 

ado-trastuzumab emtansine (T-DM1) is administered via intravenous (IV) infusion. Here are the general guidelines for the administration of T-DM1: 

• Dosage: The dosage of T-DM1 is determined based on the patient’s body weight. It is typically expressed in milligrams (mg) of T-DM1 per kilogram (kg) of body weight. 
• Preparation: T-DM1 is supplied as a lyophilized powder for reconstitution. The powder should be reconstituted with the provided diluent to prepare a solution for IV infusions.  
• Infusion: The reconstituted and diluted T-DM1 solution is administered as an IV infusion. The infusion is typically given over a specific duration, which can vary depending on the dose and the patient’s tolerance.  
• Monitoring: During the infusion, patients are closely monitored for any signs of infusion-related reactions, such as fever, chills, nausea, or difficulty breathing. Vital signs, including blood pressure, heart rate, and oxygen saturation, may be monitored regularly. 
• Frequency of Administration: The frequency of T-DM1 administration depends on the treatment plan prescribed by the healthcare provider. It is typically administered at regular intervals, such as every three weeks. The specific dosing schedule and duration of treatment will be determined based on the patient’s condition and response to therapy. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ado-trastuzumab emtansine 

Why do we use ado-trastuzumab emtansine? 

ado-trastuzumab emtansine (T-DM1) is a medication used to treat HER2-positive breast cancer. Here are the primary uses of T-DM1: 

• HER2-Positive Metastatic Breast Cancer: T-DM1 is indicated for treating HER2-positive metastatic breast cancer in patients previously receiving trastuzumab and taxane-based chemotherapy. 
• Adjuvant Treatment of HER2-Positive Early Breast Cancer: T-DM1 may be used as an adjuvant treatment for patients with HER2-positive early breast cancer who have the residual invasive disease after neoadjuvant treatment containing a taxane and trastuzumab.