Abstract 2213: Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on irinotecan, SN-38 and SN-38G pharmacokinetics.

Abstract

Abstract Background and objective: SN-38 is the active metabolite of irinotecan (CPT-11) and mainly responsible of hematological and intestinal toxicity after CPT-11 treatments. SN-38 is inactivated into SN-38G by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Some polymorphism of these enzymes leads lower clearance (CL) of SN-38 and therefore bigger exposition and bigger risk of hematological and/or intestinal toxicity (1). Therefore, the goal of this study has been to evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of CPT-11 and its metabolites, SN-38 and SN-38G on Caucassian cancer population. Methods: Plasma concentrations of CPT-11, SN-38 and SN-38G from 72 patients were pooled to develop a joint population pharmacokinetic model using NONMEM 7. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. Results: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. Clearance in patients with some allele (heterozygous or homozygous) associated with low enzymatic activity of UGT1A1*28 was a 35,7% lower (CI 95%: 6,7 - 64,7; p=0,003) than in wild-type patients. Additionally, linkage dissequilibrium indicates a strong interaction between functional UGT1A1, UGT1A7 and UGT1A9 polymorphisms related to the alteration of the UGT enzyme activity. Conclusion: The impact of UGT1A1*28 genotype on the systemic exposure of SN-38 justifies its routine determination in patients receiving CPT-11 and subsequent dose adjustment. Citation Format: Belen Valenzuela, Mario González-Sales, Vanessa Escudero, Elena Navarro, Carlos Perez-Ruixo, Joseba Rebollo, Ramon González-Manzano, Juan José Pérez-Ruixo. Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on irinotecan, SN-38 and SN-38G pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2213. doi:10.1158/1538-7445.AM2013-2213