Usage
- Medical Conditions: Trastuzumab emtansine is prescribed for the treatment of HER2-positive breast cancer. This includes:
- Metastatic breast cancer (MBC): In patients who have previously received treatment with trastuzumab and a taxane, either separately or in combination. These patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within six months of completing adjuvant therapy.
- Early breast cancer (EBC): As adjuvant treatment (after surgery) in patients with residual invasive disease after neoadjuvant (before surgery) treatment with a taxane and trastuzumab.
- Pharmacological Classification: Antineoplastic agent, antibody-drug conjugate (ADC), anti-HER2 therapy.
- Mechanism of Action: Trastuzumab emtansine is an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab linked to the cytotoxic agent mertansine (DM1). Trastuzumab targets the HER2 receptor on cancer cells, and DM1 disrupts the microtubule network within the cell, inhibiting cell division and ultimately leading to cell death.
Alternate Names
- International Nonproprietary Name (INN): Trastuzumab emtansine
- Brand Name: Kadcyla®
How It Works
- Pharmacodynamics: Trastuzumab emtansine exerts its antitumor activity through multiple mechanisms:
- HER2 receptor binding and downregulation: Trastuzumab binds to the HER2 receptor on cancer cells, inhibiting HER2 signaling pathways that promote cell growth and survival. It also facilitates receptor internalization and degradation.
- Antibody-dependent cell-mediated cytotoxicity (ADCC): Trastuzumab flags cancer cells for destruction by the immune system.
- Cytotoxic effect of DM1: After internalization of the trastuzumab-emtansine complex, DM1 is released and binds to tubulin, disrupting microtubule assembly and function. This inhibits cell division and induces apoptosis (programmed cell death).
- Pharmacokinetics:
- Absorption: Administered intravenously.
- Metabolism: DM1, the cytotoxic component, is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5. Trastuzumab itself undergoes typical antibody catabolism.
- Elimination: Both trastuzumab and DM1, as well as their metabolites, are eliminated through multiple pathways, including hepatic and renal routes. The terminal half-life of trastuzumab emtansine is approximately 4 days.
- Receptor Binding: HER2 receptor.
- Enzyme Inhibition: Microtubule polymerization inhibition through interaction with tubulin.
- Elimination Pathways: Hepatic and renal excretion, metabolism by CYP3A4/5 enzymes.
Dosage
Standard Dosage
Adults:
- 3.6 mg/kg body weight administered as a 90-minute intravenous infusion every 3 weeks (21-day cycle).
Children:
- No established dosage. Safety and efficacy have not been established in pediatric patients.
Special Cases:
- Elderly Patients (≥ 65 years): No dose adjustment is required for patients aged 65 to <75 years. Limited data are available for patients ≥ 75 years.
- Patients with Renal Impairment: No dose adjustment is recommended for mild to moderate renal impairment. Limited data are available for patients with severe renal impairment.
- Patients with Hepatic Dysfunction: Monitor liver function closely. Dose modifications are recommended for moderate to severe hepatic impairment or hepatotoxicity.
- Patients with Comorbid Conditions: Exercise caution in patients with pre-existing cardiac dysfunction, left ventricular ejection fraction (LVEF) ≤50%, or those experiencing dyspnea at rest.
Clinical Use Cases
Trastuzumab emtansine is not typically used in the context of intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations like status epilepticus or cardiac arrest. Its primary indication is for HER2-positive breast cancer.
Dosage Adjustments
Dose reductions may be necessary based on adverse events, including hepatotoxicity, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, and peripheral neuropathy. Refer to the prescribing information for specific dose modification guidelines.
Side Effects
Common Side Effects:
- Nausea, fatigue, musculoskeletal pain, bleeding or bruising, headache, thrombocytopenia, elevated liver enzymes, peripheral neuropathy, numbness and tingling in fingers and toes.
Rare but Serious Side Effects:
- Hepatotoxicity (liver damage), including liver failure and death
- Cardiomyopathy (heart muscle weakness)
- Thrombotic thrombocytopenic purpura (TTP)
- Interstitial lung disease (ILD)/Pneumonitis
- Anaphylaxis (severe allergic reaction)
- Embryofetal toxicity
Long-Term Effects:
- Potential for long-term cardiac effects and peripheral neuropathy.
Adverse Drug Reactions (ADR):
- Any severe or life-threatening side effects as mentioned above.
Contraindications
- Hypersensitivity to trastuzumab emtansine or any of its components.
- Pregnancy.
Drug Interactions
- CYP3A4 Inhibitors: Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) may increase DM1 exposure and toxicity. Avoid concomitant use or closely monitor for adverse reactions.
- CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g., rifampin, St. John’s wort) might decrease DM1 exposure.
- Anthracyclines: Do not administer anthracyclines concurrently with or within 6 months of the last dose of trastuzumab emtansine.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D. Trastuzumab emtansine can cause fetal harm and is contraindicated during pregnancy. Effective contraception is mandatory during treatment and for 7 months after the last dose for female patients and their male partners.
- Breastfeeding: It is unknown whether trastuzumab emtansine is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment and for 7 months after the last dose.
Drug Profile Summary
- Mechanism of Action: HER2 receptor binding and downregulation; ADCC; microtubule disruption by DM1.
- Side Effects: Nausea, fatigue, musculoskeletal pain, bleeding/bruising, hepatotoxicity, cardiomyopathy, peripheral neuropathy.
- Contraindications: Hypersensitivity, pregnancy.
- Drug Interactions: Strong CYP3A4 inhibitors and inducers, anthracyclines.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding should be discontinued.
- Dosage: 3.6 mg/kg IV every 3 weeks.
- Monitoring Parameters: LVEF, liver function tests, complete blood counts, signs of hypersensitivity.
Popular Combinations
Trastuzumab emtansine is typically used as a single agent. It is not commonly used in combination with other chemotherapy agents in the settings described.
Precautions
- General Precautions: Assess HER2 status before starting treatment. Monitor LVEF, liver function tests, and complete blood counts. Observe patients for infusion-related reactions and hypersensitivity.
- Specific Populations: Pregnant women (contraindicated), breastfeeding mothers (discontinue breastfeeding), children (no established safety and efficacy), elderly (limited data for patients ≥ 75 years).
- Lifestyle Considerations: Patients should avoid activities requiring alertness until the effects of the drug are known.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Trastuzumab Emtansine?
A: 3.6 mg/kg administered as an intravenous infusion every 3 weeks.
Q2: How is Trastuzumab Emtansine administered?
A: As a 90-minute intravenous infusion. The infusion site should be closely monitored for extravasation.
Q3: What are the most common side effects of Trastuzumab Emtansine?
A: Nausea, fatigue, musculoskeletal pain, bleeding/bruising, elevated liver enzymes, and peripheral neuropathy.
Q4: What are the serious side effects to watch out for with Trastuzumab Emtansine?
A: Hepatotoxicity, cardiomyopathy, thrombotic thrombocytopenic purpura, interstitial lung disease/pneumonitis, and anaphylaxis.
Q5: Can Trastuzumab Emtansine be used during pregnancy?
A: No, it is contraindicated in pregnancy due to the risk of fetal harm.
Q6: Can a patient breastfeed while taking Trastuzumab Emtansine?
A: No, breastfeeding should be discontinued during treatment and for 7 months following the last dose.
Q7: What should be monitored in patients receiving Trastuzumab Emtansine?
A: Left ventricular ejection fraction (LVEF), liver function tests (LFTs), complete blood count (CBC), and signs and symptoms of hypersensitivity or infusion-related reactions.
Q8: How does Trastuzumab Emtansine differ from Trastuzumab?
A: Trastuzumab emtansine is an antibody-drug conjugate combining trastuzumab with the cytotoxic agent DM1. Trastuzumab alone does not contain a cytotoxic component.
Q9: What are the key drug interactions with Trastuzumab Emtansine?
A: Strong CYP3A4 inhibitors and inducers may alter DM1 exposure. Concomitant use of anthracyclines is contraindicated.
