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The Role of UGT1A1*28 Polymorphism in the Pharmacodynamics and Pharmacokinetics of Irinotecan in Patients With Metastatic Colorectal Cancer

2006; Lippincott Williams & Wilkins; Volume: 24; Issue: 19 Linguagem: Inglês

10.1200/jco.2005.05.5400

1527-7755

Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona, Antonio Russo, Angela Buonadonna, Mario D’Andrea, Lara Maria Pasetto, S. Pessa, D. Errante, V. De Pangher, Mauro Giusto, Michele Medici, Fernando Gaion, Paolo Sandri, Enzo Galligioni, Salvatore Bonura, M. Boccalon, Paola Biason, S. Frustaci,

Antibiotics Pharmacokinetics and Efficacy

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)×(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.