Ado-trastuzumab emtansine

Usage

• Ado-trastuzumab emtansine is prescribed for HER2-positive breast cancer. This includes:
  • Metastatic breast cancer (MBC): For patients who have previously received trastuzumab and a taxane, separately or in combination, and have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.
  • Early breast cancer (EBC) adjuvant treatment: For patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
• Pharmacological Classification: Antineoplastic agent, antibody-drug conjugate (ADC), HER2-targeted therapy.
• Mechanism of Action: Ado-trastuzumab emtansine is an ADC that targets the HER2 receptor. The trastuzumab component binds to HER2 on the surface of cancer cells, and the emtansine (DM1) component, a cytotoxic agent, is internalized into the cell. DM1 inhibits microtubule polymerization, disrupting cell division and leading to cell death.

Alternate Names

• International Nonproprietary Name (INN): Trastuzumab emtansine
• Brand Name: Kadcyla

How It Works

• Pharmacodynamics: Ado-trastuzumab emtansine selectively targets HER2-positive cancer cells. The emtansine component disrupts microtubule function, leading to cell cycle arrest and apoptosis (programmed cell death).
• Pharmacokinetics: Ado-trastuzumab emtansine is administered intravenously. The trastuzumab component exhibits nonlinear pharmacokinetics. Emtansine is released intracellularly and is primarily metabolized by CYP3A4. Elimination occurs mainly through hepatic routes, with some renal excretion.
• Mode of Action: Receptor binding (HER2), microtubule inhibition.
• Elimination Pathways: Primarily hepatic metabolism (CYP3A4) and biliary excretion.

Dosage

Standard Dosage

Adults:

• MBC and EBC: 3.6 mg/kg administered as an intravenous infusion every 3 weeks (21-day cycle). Do not exceed 3.6 mg/kg. Continue until disease progression or unacceptable toxicity (MBC) or for 14 cycles (EBC) unless there is disease recurrence or unacceptable toxicity. In patients with EBC who did not receive prior neoadjuvant therapy, treatment may be extended to 17 cycles. The initial dose should be infused over 90 minutes; if well tolerated, subsequent infusions may be administered over 30 minutes.

Children: No established dosing guidelines. Safety and efficacy have not been established in pediatric patients.

Special Cases:

• Elderly Patients: No specific dose adjustment is required based on age.
• Patients with Renal Impairment: No dose adjustment is recommended.
• Patients with Hepatic Dysfunction: Dose reductions may be necessary. Monitor liver function closely.
• Patients with Comorbid Conditions: Monitor closely for adverse events, especially in patients with pre-existing cardiac conditions.

Clinical Use Cases

Ado-trastuzumab emtansine is specifically indicated for HER2-positive breast cancer (MBC and EBC adjuvant treatment). It is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dose reductions may be required based on adverse events, particularly hepatotoxicity, left ventricular dysfunction, thrombocytopenia, and peripheral neuropathy. Refer to the prescribing information for specific dose reduction schedules.

Side Effects

Common Side Effects

Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, constipation, peripheral neuropathy.

Rare but Serious Side Effects

Hepatotoxicity (including liver failure), left ventricular dysfunction (including heart failure), infusion-related reactions, thrombocytopenia, pulmonary toxicity (including pneumonitis), peripheral neuropathy (can be severe), embryo-fetal toxicity.

Long-Term Effects

Potential long-term effects may include cardiac dysfunction and peripheral neuropathy.

Adverse Drug Reactions (ADR)

Hepatotoxicity, cardiac dysfunction, infusion-related reactions, severe thrombocytopenia, pulmonary toxicity, severe peripheral neuropathy.

Contraindications

None.

Drug Interactions

Strong CYP3A4 inhibitors may increase DM1 exposure and toxicity. Concomitant use should be avoided. If unavoidable, closely monitor for adverse reactions.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D. Ado-trastuzumab emtansine can cause fetal harm and death.
• Fetal Risks: Oligohydramnios, pulmonary hypoplasia, skeletal abnormalities, neonatal death.
• Breastfeeding: Ado-trastuzumab emtansine may be excreted in breast milk and can cause serious adverse reactions in breastfed infants. Breastfeeding is contraindicated during treatment and for 7 months after the last dose.

Drug Profile Summary

• Mechanism of Action: HER2-targeted antibody-drug conjugate that inhibits microtubules, leading to cancer cell death.
• Side Effects: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, peripheral neuropathy. Serious side effects: hepatotoxicity, cardiac dysfunction, infusion reactions, pulmonary toxicity.
• Contraindications: None.
• Drug Interactions: Strong CYP3A4 inhibitors.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 3.6 mg/kg IV every 3 weeks.
• Monitoring Parameters: LVEF, liver function tests, platelet counts, signs of pulmonary toxicity and peripheral neuropathy.

Popular Combinations

Ado-trastuzumab emtansine is typically used as a single agent.

Precautions

• Evaluate LVEF and liver function prior to and during treatment.
• Monitor platelet counts prior to each dose.
• Monitor for signs and symptoms of pulmonary toxicity and peripheral neuropathy.
• Females of reproductive potential should use effective contraception.
• Males with female partners of reproductive potential should use effective contraception.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ado-trastuzumab emtansine?

A: 3.6 mg/kg IV every 3 weeks (21-day cycle) for MBC or for 14 cycles for EBC (may be extended up to 17 cycles if the patient did not receive neoadjuvant treatment).

Q2: What are the most common side effects?

A: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, elevated liver enzymes, and constipation.

Q3: What are the serious side effects to watch for?

A: Hepatotoxicity, cardiotoxicity, infusion-related reactions, thrombocytopenia, pulmonary toxicity, and peripheral neuropathy.

Q4: Can Ado-trastuzumab emtansine be given during pregnancy?

A: No. It is contraindicated during pregnancy due to the risk of fetal harm and death.

Q5: Is it safe to breastfeed while taking Ado-trastuzumab emtansine?

A: No. Breastfeeding is contraindicated during treatment and for 7 months following the last dose.

Q6: What should be monitored before and during treatment?

A: Left ventricular ejection fraction (LVEF), liver function tests, complete blood counts (especially platelets), and monitor for signs of pulmonary toxicity and peripheral neuropathy.

Q7: What are the key drug interactions?

A: Avoid concomitant use with strong CYP3A4 inhibitors as they can increase the risk of toxicity.

Q8: How is Ado-trastuzumab emtansine administered?

A: As an intravenous infusion, initially over 90 minutes, then over 30 minutes if tolerated.

Q9: How long is a typical course of treatment for early breast cancer (EBC)?

A: 14 cycles, given every 3 weeks, unless there is disease recurrence or unacceptable toxicity. May be extended to 17 cycles in patients who did not receive prior neoadjuvant therapy.