The role of UGT1A1*28 polymorphism in the pharmacodynarnics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer

Purpose UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent. Patients and Methods In a prospective study, 250 metastatic colorectal cancer patients.-were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic,and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy. Results UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA(7)/TA(7) compared with wild-type TA(6)/TA(6). The response rate was also higher in TA(7)TA(7) patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA(6)/TA(6). A nonsignificant survival advantage was observed for TA(7)/TA(7) when compared with TA(6)/TA(6) patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)X(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA(7)/TA(7) genotype and a higher response rate, indicating that the polymorphism is functionally relevant. Conclusion The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the,result of this analysis.