Chemical Class:
- A potent topoisomerase I inhibitor and a derivative of exatecan.
Mechanism of Action:
- Inhibits topoisomerase I enzyme, which is essential for relieving DNA supercoiling during replication and transcription.
- Inhibition causes DNA strand breaks leading to DNA damage, replication arrest, and apoptosis of cancer cells.
Role in Antibody-Drug Conjugates (ADCs):
- Used as the cytotoxic payload in ADCs such as fam-trastuzumab deruxtecan (Enhertu).
- The drug is linked via a cleavable linker to a monoclonal antibody targeting HER2, enabling targeted delivery to HER2-expressing tumor cells.
- Once internalized, deruxtecan is released inside tumor cells, maximizing tumor cell kill while minimizing systemic toxicity.
- Deruxtecan’s membrane permeability allows for a bystander effect, killing neighboring cancer cells regardless of HER2 expression.
Pharmacist Considerations:
- Deruxtecan is highly potent; toxicity mainly arises when used in ADC form.
- Associated with hematologic toxicities (neutropenia, anemia, thrombocytopenia) and interstitial lung disease (ILD) when used in ADCs.
- Monitoring and early recognition of adverse effects are crucial to minimize serious toxicities.
- No direct systemic administration of deruxtecan alone; always given conjugated in ADC format.