kadcyla

Indications

• HER2-positive breast cancer
• Metastatic breast cancer

Dosage

Children: Refer to the BNF for Children for appropriate dosing information in paediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on the patient's condition and response to therapy.

Mechanism of action

Emtansine is a conjugate of trastuzumab (a monoclonal antibody targeting HER2) linked to a microtubule inhibitor (DM1). The mechanism involves the binding of the antibody to HER2-positive cells, facilitating the internalization of the conjugate. Once inside the cell, DM1 is released, leading to disruption of microtubule dynamics, inhibition of cell division, and ultimately inducing apoptosis in the target cancer cells.

Pharmacodynamics

Emtansine exhibits its effects through selective targeting of HER2-positive cells, resulting in potent cytotoxicity. The drug's therapeutic efficacy is associated with its ability to interfere with the microtubule network necessary for mitosis, leading to cell cycle arrest and apoptosis. The selectivity of emtansine for HER2-positive cells reduces the risk of damage to normal cells, enhancing its safety profile compared to conventional chemotherapeutics.

Pharmacokinetics

After administration, emtansine is distributed throughout the body, with a volume of distribution that indicates extensive tissue binding. The drug undergoes metabolism primarily via hepatic pathways, and its elimination half-life is influenced by the conjugated antibody. Emtansine is cleared from the body through both renal and biliary pathways, with a longer half-life allowing for less frequent dosing compared to traditional chemotherapeutics.

Adverse effects

• Nausea
• Vomiting
• Fatigue
• Thrombocytopenia
• Hepatotoxicity
• Peripheral neuropathy

Interactions

• CYP3A4 inhibitors may increase the risk of adverse effects
• CYP3A4 inducers may decrease efficacy

Precautions

• Monitor liver function tests regularly
• Assess for signs of peripheral neuropathy
• Use caution in patients with a history of hypersensitivity reactions

Pregnancy

Should not be used during pregnancy due to potential harm to the fetus.

Breast-feeding

Not recommended while breastfeeding due to potential risk to the infant.

Storage

Store at 2 to 8 degrees Celsius. Protect from light.

Formulations

• Injection for intravenous use

Indications

• Metastatic breast cancer in patients with HER2 overexpression who have received at least two prior chemotherapy regimens, including an anthracycline and a taxane.
• Metastatic gastric cancer in patients with HER2-positive tumors who have not received prior treatment for this condition.

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients, as specific doses are not provided in the BNF.

Adults: The recommended dosage for adults is typically 8 mg/kg as a loading dose, followed by 6 mg/kg every three weeks, administered via intravenous infusion or subcutaneous injection.

Mechanism of action

Trastuzumab binds specifically to the extracellular domain of the human epidermal growth factor receptor 2 (HER2), leading to inhibition of HER2-mediated signaling pathways, including the PI3K/AKT and MAPK pathways. This blockade reduces cell proliferation and induces apoptosis in HER2-overexpressing cells. Additionally, trastuzumab enhances antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells.

Pharmacodynamics

Trastuzumab demonstrates a dose-dependent effect on inhibiting the growth of HER2-positive cancer cells. Its clinical efficacy is primarily associated with its ability to target HER2 overexpression, leading to decreased tumor growth and improved survival rates in patients with HER2-positive breast and gastric cancers. Common side effects include infusion-related reactions, gastrointestinal disturbances, and increased risk of infections.

Pharmacokinetics

Trastuzumab has a terminal half-life of approximately 5 to 8 days after the initial intravenous administration. It is distributed widely, with a volume of distribution typically around 2-3 L/kg. Metabolism occurs via proteolytic degradation, primarily in the reticuloendothelial system. The clearance is affected by the patient's body size and HER2 expression levels, and it is excreted mainly through the lymphatic system.

Contra-indications

• Severe dyspnoea at rest
• Symptomatic heart failure
• Uncontrolled arrhythmias

Adverse effects

• Abdominal pain
• Alopecia
• Anaemia
• Appetite decreased
• Arthralgia
• Asthenia
• Constipation
• Cough exacerbated
• Decreased leucocytes
• Diarrhoea
• Dyspnoea
• Electrolyte imbalance
• Fever
• Headache
• Hyperbilirubinaemia
• Hyperhidrosis
• Hypogammaglobulinaemia
• Increased risk of infection
• Infusion related reaction
• Malaise
• Mucositis
• Muscle spasms
• Nasal congestion
• Nausea
• Neutropenia
• Pain
• Paresthesia
• Peripheral oedema
• Sepsis
• Skin reactions
• Taste altered
• Thrombocytopenia
• Vomiting
• Weight decreased

Interactions

• Anthracyclines: Severe (increases risk of cardiotoxicity)
• Anthracyclines + trastuzumab-emtansine: Severe (increases risk of cardiotoxicity)
• Cobicistat + trastuzumab-emtansine: Severe (increases exposure)
• Idelalisib + trastuzumab-emtansine: Severe (increases exposure)
• Clarithromycin + trastuzumab-emtansine: Severe (increases exposure)
• Anthracyclines + trastuzumab-deruxtecan: Unknown (increases risk of cardiotoxicity)

Precautions

• Monitor for cardiac function before each treatment cycle and throughout therapy
• Females of childbearing potential should use effective contraception during treatment and for at least 3 months after last treatment

Pregnancy

Use is not recommended during pregnancy. If exposed, monitor the infant for B-cell depletion.

Breast-feeding

It is not known if trastuzumab is excreted in human milk. Caution should be exercised.