How does UGT1A1 (Uridine Diphosphate Glucuronosyltransferase 1A1) polymorphism affect Irinotecan (Camptothecin-11) therapy?

UGT1A1 Polymorphism and Irinotecan Therapy

*UGT1A1 genotyping should be performed before initiating irinotecan therapy, with a 25-30% dose reduction recommended for patients homozygous for UGT1A128 (28/28) to reduce the risk of severe neutropenia while maintaining therapeutic efficacy. 1, 2

Impact of UGT1A1 Polymorphisms on Irinotecan Metabolism

• UGT1A1 enzyme is responsible for glucuronidation of SN-38 (the active metabolite of irinotecan) to its inactive form SN-38G 3
• The UGT1A1*28 variant, characterized by an extra TA repeat in the promoter region [(TA)7TAA instead of (TA)6TAA], results in reduced enzyme expression 3
• Homozygous UGT1A1*28 carriers (*28/*28) have 50-70% reduction in enzyme activity compared to wild-type, leading to higher exposure to active SN-38 3
• Heterozygous carriers (*1/*28) have approximately 25% reduction in enzyme activity 3
• UGT1A1*28 homozygosity occurs in approximately 10% of North American population, with variable prevalence depending on race 3

Clinical Implications for Adverse Events

Neutropenia Risk

• Homozygous UGT1A1*28 carriers have a 3.5-fold increased risk of severe (Grade 3/4) neutropenia compared to wild-type patients (38% vs. 9.8%) 3
• Heterozygous carriers have a 1.8-fold increased risk (18% vs. 9.8%), though this increase is not statistically significant 3
• The association between UGT1A1*28 and neutropenia is dose-dependent, with significant risk at irinotecan doses ≥150 mg/m² 3

Diarrhea Risk

• The association between UGT1A1*28 and severe diarrhea is weaker than for neutropenia 3
• Homozygous carriers have a 1.6-fold increased risk of severe diarrhea (27% vs. 18%), though this is not statistically significant 3
• Heterozygous carriers have a 1.4-fold increased risk (27% vs. 18%), also not statistically significant 3

Tumor Response and Efficacy

• At standard doses, homozygous UGT1A1*28 carriers show significantly higher tumor response rates compared to wild-type patients (70% vs. 41%, risk ratio 1.70) 3
• This suggests wild-type patients may be relatively under-dosed at standard irinotecan doses 3
• Heterozygous carriers show similar response rates to wild-type (45% vs. 41%) 3

Dosing Recommendations

For UGT1A1*28 Homozygous Patients (*28/*28)

• FDA-approved irinotecan labeling recommends dose reduction for UGT1A1*28 homozygous patients 1
• A 25-30% reduction in starting dose is generally recommended for these patients 2
• The precise dose reduction is not definitively established; subsequent dose modifications should be based on individual tolerance 1

For UGT1A1*28 Heterozygous Patients (*1/*28)

• For heterozygous patients, a more modest dose reduction (approximately 20%) may be considered, especially when using higher irinotecan doses 4
• Close monitoring for toxicity is essential in these patients 1

Dose Considerations Based on Treatment Regimen

• UGT1A1 genotyping may not be warranted for regimens using lower irinotecan doses (<150 mg/m²) 3
• Testing is most valuable for regimens using irinotecan at doses ≥150 mg/m² or when combined with other myelotoxic agents 3

Clinical Utility of UGT1A1 Testing

• Pre-therapeutic UGT1A1 genotyping improves patient safety and is likely to be cost-effective 2
• No prospective studies have directly documented clinical outcomes when treatment is guided by UGT1A1 genotyping versus empirical treatment 3
• UGT1A1 testing in patients who have already experienced irinotecan toxicity is not recommended, as they will require dose reduction regardless of genotype 3

Other Considerations

• Other UGT1A1 variants such as UGT1A1*6 are also clinically relevant, particularly in Asian populations 5
• Patients with Gilbert syndrome or elevated serum bilirubin should receive irinotecan with caution and at decreased doses 3
• For patients receiving high-dose irinotecan with high risk of febrile neutropenia (≥20%), prophylactic use of colony-stimulating factors may be considered 3

Practical Approach

1. Consider UGT1A1 genotyping before initiating irinotecan therapy, particularly for regimens using doses ≥150 mg/m² 3, 2
2. Reduce initial irinotecan dose by 25-30% for UGT1A1*28 homozygous patients 1, 2
3. Consider modest dose reduction (approximately 20%) for heterozygous patients, especially with higher-dose regimens 4
4. Monitor all patients closely for neutropenia and diarrhea, with particular vigilance for homozygous patients 1
5. Adjust subsequent doses based on individual tolerance 1