Irinotecan

Irinotecan is a chemotherapeutic medication used primarily in the treatment of colorectal cancer and other solid tumors. It is a topoisomerase I inhibitor and is marketed under the brand names Camptosar and Onivyde.

Irinotecan is approved for metastatic colorectal cancer and small cell lung cancer, among other malignancies. It is often used in combination with other agents to enhance anticancer efficacy.

The drug works by inhibiting topoisomerase I, an enzyme essential for DNA replication and repair. This inhibition leads to DNA damage in rapidly dividing cancer cells, ultimately causing cell death.

UGT1A1 is the primary gene associated with irinotecan metabolism. It encodes the enzyme uridine diphosphate glucuronosyltransferase 1A1, which adds a glucuronic acid moiety to SN-38 (the active metabolite of irinotecan) to facilitate its elimination.

Variants in UGT1A1 that reduce enzyme activity can lead to decreased glucuronidation and clearance of SN-38, resulting in higher systemic concentrations of the active metabolite. This increased exposure is associated with a greater risk of adverse effects such as severe neutropenia and diarrhea.

Individuals are categorized based on UGT1A1 activity into normal, intermediate, or poor metabolizers. Reduced-function alleles decrease SN-38 clearance, increasing toxicity risk, while normal function maintains expected drug exposure. In some cases, high-function alleles may decrease efficacy, though these are less common.

Ultra-rapid/Rapid Metabolizer

• Effect on drug levels: Lower than expected systemic SN-38 levels
• Clinical consequence: Potential reduced anticancer efficacy
• Side effects: Decreased incidence of neutropenia and diarrhea (mild)

Normal Metabolizer

• Effect on drug levels: Expected systemic SN-38 levels
• Clinical consequence: Standard efficacy and toxicity profile
• Side effects: Typical rates of neutropenia and diarrhea

Intermediate Metabolizer

• Effect on drug levels: Moderately increased SN-38 levels
• Clinical consequence: Slightly higher risk of toxicity
• Side effects: Moderate neutropenia and diarrhea, may require monitoring

Poor Metabolizer

• Effect on drug levels: Significantly increased SN-38 levels
• Clinical consequence: High risk of severe neutropenia and diarrhea
• Side effects: Severe neutropenia and diarrhea, frequent and potentially life-threatening

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
• Side effects: Uncertain; monitor for typical irinotecan-related toxicities

UGT1A1 Dosing Guideline

Examples from oncology practice include using oxaliplatin-based regimens (e.g., FOLFOX) or alternative topoisomerase inhibitors such as topotecan. These are provided as examples and not specific medical advice.

• FDA – Table of Pharmacogenetic Associations