Irinotecan and uridine diphosphate glucuronosyltransferase 1A1 pharmacogenetics: to test or not to test, that is the...

Pharmacogenetic research indicates a relationship between a polymorphism in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and irinotecan inactivation, in that degradation of SN-38, the active metabolite of irinotecan, correlates inversely with the number of TA repeats in the TATA element of the UGT1A1 promoter region. Individuals who are homozygous for the UGT1A1*28 allele (7 repeats) may exhibit reduced degradation of SN-38 and increased probability of severe toxicities. Clinical study results, as reported in the literature, have not been uniform, however, in showing a relation between genotype and the development of toxicities. Even when correlations are statistically significant, confidence intervals are wide, rendering assessment of individual risk difficult at best. Irinotecan labeling recommends testing for the UGT1A1*28 allele and reducing irinotecan dosing in patients who are positive to reduce the likelihood of dose-limiting neutropenia only, but not diarrhea. Importantly, both dose-limiting neutropenia and diarrhea are dependent on numerous known and unknown factors, such as the specific regimen used, duration of therapy, doses, cycle of treatment, and complexities of irinotecan pharmacodynamics and pharmacokinetics, including other key enzymes and drug transporters. Guidance on how to modify irinotecan dosing or how to incorporate the impact of multiple variables into clinical decision-making does not exist. Furthermore, pharmacogenomic test results at this time can only provide an estimate of risk for subsets of populations rather than a risk-benefit estimate for an individual. Consequently, these test results are supplementary to clinical judgment, which requires assessing multiple variables that contribute to phenotype to arrive at individual dosing decisions.