- Class: Plant alkaloid (semisynthetic camptothecin derivative).
- Pharmacological group: Topoisomerase I inhibitor.
Mechanism of Action (MOA)
- Prodrug → converted by carboxylesterases in the liver to SN-38 (active metabolite).
- SN-38 binds to the topoisomerase I–DNA complex, preventing religation of single-strand breaks.
- Leads to irreversible DNA damage and apoptosis.
- Cell cycle–specific: active in the S-phase.
Clinical Uses
- Metastatic colorectal cancer (first-line with 5-FU/leucovorin = FOLFIRI regimen).
- Pancreatic cancer (liposomal irinotecan + 5-FU/LV after gemcitabine).
- Off-label: lung cancers, gastric cancer, CNS tumors (protocol-dependent).
Dosing (Adults)
- Camptosar®:
- Colorectal cancer (FOLFIRI): 180 mg/m² IV q2w.
- Single-agent: 125 mg/m² IV weekly × 4, q6w cycle.
- Onivyde® (liposomal): 70 mg/m² IV q2w (pancreatic cancer, with 5-FU/LV).
- Dose adjustments required for UGT1A1*28 polymorphism, hepatic impairment, or severe neutropenia/diarrhea.
Toxicities
- Dose-limiting:
- Diarrhea (two types):
- Early-onset (within 24h, cholinergic → treat with atropine).
- Late-onset (days later, secretory → can be life-threatening → treat with loperamide, hydration).
- Myelosuppression (esp. neutropenia).
- Diarrhea (two types):
- Nausea, vomiting, mucositis, alopecia, fatigue.
- Rare: interstitial lung disease.
Monitoring
- CBC with differential (neutropenia).
- Bowel patterns (for diarrhea severity).
- LFTs (hepatic metabolism).
- Consider UGT1A1*28 genetic testing (↑ toxicity risk due to impaired SN-38 glucuronidation).
Summary
Irinotecan is a Topoisomerase I inhibitor, key in FOLFIRI for colorectal cancer. Its hallmark toxicity is diarrhea (early atropine-responsive vs late loperamide-responsive), along with myelosuppression. Pharmacogenetics (UGT1A1*28) play a major role in toxicity risk.