trastuzumab/deruxtecan

Action and Spectrum

Actions and Spectrum: 

Actions: 

• Targeted HER2 Inhibition: trastuzumab/deruxtecan utilizes trastuzumab, a monoclonal antibody, to target the HER2 protein overexpressed in specific cancer cells. trastuzumab binds to the HER2 receptors on cancer cells, inhibiting the signaling pathways that promote cancer cell growth and division. 
• Antibody-Drug Conjugate (ADC): trastuzumab/deruxtecan combines the targeted action of trastuzumab with the cytotoxic effect of deruxtecan, a topoisomerase I inhibitor. The ADC allows selective delivery of the cytotoxic agent to HER2-positive cancer cells. 
• Payload Delivery and Cell Death: The deruxtecan component of trastuzumab/deruxtecan is released within the cancer cell after the ADC binds to the HER2 receptor. deruxtecan inhibits topoisomerase I, an enzyme involved in DNA replication and repair. This inhibition leads to DNA damage and ultimately results in cancer cell death. 

Spectrum: 

• Locally advanced or metastatic HER2-positive breast cancer: trastuzumab/deruxtecan is approved for the treatment of metastatic HER2-positive breast cancer in the patients who have received two or more prior anti-HER2 therapies (such as trastuzumab and pertuzumab) in the metastatic setting. It is used after the disease has progressed after prior treatment regimens or when other treatment options have been exhausted. 

Drug Interaction

Adverse Reaction

Adverse reactions 

Frequency defined  

>10% 

Nausea (76%) 

Decreased white blood cell count (WBC) (74%) 

Decreased hemoglobin (64%) 

Decreased lymphocyte count (55%) 

Increased ALT (53%) 

Decreased neutrophil count (70%) 

Increased AST (67%) 

Decreased platelet count (52%) 

Vomiting (49%) 

Hypokalemia (35%) 

Constipation (34%) 

Anemia (33%) 

Increased blood alkaline phosphatase (49%) 

Fatigue (49%) 

Alopecia (37%) 

Musculoskeletal pain (31%) 

Respiratory tract infection (22%) 

Headache (22%) 

Diarrhea (29%) 

Decreased appetite (29%) 

Abdominal pain (21%) 

Increased blood bilirubin (20%) 

Stomatitis (20%) 

Decreased neutrophil count, Grade 3 or 4 (18%) 

Decreased lymphocyte count, Grade 3 or 4 (14%) 

Peripheral neuropathy (13%) 

Dizziness (13%) 

Decreased weight (17%) 

Increased blood creatinine (0.8%) 

1-10% 

Rash (10%) 

Vomiting, Grade 3 or 4 (3.8%) 

Hypokalemia (3.3%) 

Dizziness (10%) 

Interstitial lung disease (9%) 

Increased blood bilirubin (2.7%) 

<1% 

Increased ALT, Grade 3 or 4 (0.8%) 

Alopecia, Grade 3 or 4 (0.4%) 

Constipation, Grade 3 or 4 (0.9%) 

Stomatitis, Grade 3 or 4 (0.9%) 

Dry eye, Grade 3 or 4 (0.4%) 

Black Box Warning

Black Box Warning: 

The drug may lead to pneumonitis, embryo-fetal toxicity, and pulmonary toxicity.

Contraindication / Caution

Contraindication/Caution: 

Contraindications 

• Hypersensitivity 

Caution 

• Cardiotoxicity 
• Interstitial lung disease 
• Hematological toxicity 
• Hepatic impairment 
• Renal impairment 
• Infusion reactions 
• Pregnancy  
• Breastfeeding 
• Other conditions 

Pregnancy / Lactation

Pregnancy consideration:  

No adequate data are available regarding the usage of the drug during pregnancy. Based on the mechanism of action, the drug shows fetal toxicity. 

Breastfeeding warnings:  

No data on the drug’s effect on the infant during breastfeeding is available. 

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: No data is available for the drug under this category. 

Pharmacology

Pharmacology  

• Selective Targeting: trastuzumab, the antibody component, binds to the HER2 receptor, which is overexpressed in HER2-positive breast cancer cells. This binding specifically targets the cancer cells while sparing normal cells. 
• Internalization: Upon binding to the HER2 receptor, trastuzumab/deruxtecan is internalized into the cancer cell through receptor-mediated endocytosis. 
• Payload Release: Within the cancer cell, deruxtecan, the cytotoxic payload, is released from the ADC. deruxtecan is a topoisomerase I inhibitor that inhibits the DNA repair process. 
• DNA Damage and Cell Death: deruxtecan inhibits the action of topoisomerase I, an enzyme involved in DNA replication and repair. This leads to the accumulation of DNA damage, which results in cancer cell death.

Pharmacodynamics 

The pharmacodynamics of trastuzumab/deruxtecan is primarily driven by its targeted action on HER2-positive cancer cells. The binding of trastuzumab to HER2 receptors inhibits downstream signaling pathways involved in cancer cell growth and survival. Release of deruxtecan within the cancer cell leads to DNA damage and cell death.  

Pharmacokinetics 

Absorption 

trastuzumab/deruxtecan is administered intravenously, resulting in rapid and complete systemic exposure. 

Distribution 

trastuzumab, the antibody component, exhibits a distribution pattern similar to other monoclonal antibodies. The volume of distribution is large and can distribute to various tissues, including tumor tissues. 

Metabolism 

The deruxtecan component of trastuzumab/deruxtecan is metabolized by enzymes, primarily hepatic enzymes such as cytochrome P450 (CYP).  

Elimination and Excretion 

trastuzumab/deruxtecan is eliminated through multiple pathways. The deruxtecan component undergoes hepatic metabolism, while the antibody component is eliminated through proteolytic degradation 

Adminstartion

Administration 

trastuzumab/deruxtecan is administered via intravenous infusion. It is delivered directly into a vein through a needle or a central venous access device, such as a catheter. 

Infusion Schedule: 

The infusion schedule for trastuzumab/deruxtecan typically involves a specific number of weeks of treatment. The medication is administered on a set schedule, including multiple doses over several weeks or months. The duration of each infusion and the interval between cycles can vary based on the treatment protocol prescribed by the healthcare provider. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: trastuzumab/deruxtecan 

Pronounced: tras-TOO-zoo-mab DEH-rux-TEE-kan)  

Why do we use trastuzumab/deruxtecan? 

trastuzumab/hyaluronidase is a medication used to treat HER2-positive breast cancer. It’s important to note that trastuzumab/deruxtecan should be thoroughly evaluated based on the patient’s condition, including HER2 status, treatment history, overall health, and individual treatment goals.