L.C. Mbatchi(1)(2), S. Khier(3), J. Robert(4), A. Iliadis(5), A. Evrard(1)(2)
(1) Biochemistry and Toxicology division, University Hospital CAREMEAU, Nîmes, France; (2) Institut de Genomique Fonctionnelle CNRS UMR5203 INSERM U661, Université Montpellier 1 et 2, Montpellier; (3) Pharmacokinetic Department, Université Montpellier 1, France (4) Institut Bergonié, Bordeaux, France ; (5) Pharmacokinetic Department, Université Aix-Marseille, France
Objectives: Irinotecan is an anticancer agent broadly used in the treatment of colorectal cancer. The main genetic factor associated with the PK variability of CPT11 is a UGT1A1 polymorphism (UGT1A1*28)1, the enzyme which detoxify the active metabolite (SN38) into an inactive glucuronide form (SN38G). The xenoreceptors PXR (gene NR1I2) and CAR (gene NR1I3) are the transcriptional regulators of all the genes which control the CPT11 metabolism, including UGT1A1. We hypothesize that polymorphisms of PXR and CAR can explain a part of the variability of the PK of irinotecan.
Methods: A population pharmacokinetic analysis was performed using Monolix™ based on plasma samples from 109 patients traited by FOLFIRI (leuvocorin, 5FU and irinotecan). Four sequential models of Irinotecan and each of its metabolites have been designed. We made a selection of 13 SNPs ( Single Nucleotide Polymorphism) of NR1I2 and 6 SNPs of NR1I3, selected on the basis of their association with the PK of other drugs in the literature2 or as tagSNP to ensure good coverage of the genetic variability of these genes (Haploview™ Software). Then, an exploratory study of genetic covariables was conducted by testing the association between the empirical Bayesian estimation of the parameter of irinotecan and metabolites with the genotype of the patients for UGT1A1*28, NR1I2, and NR1I3. For the single locus analysis, we used the SNPassoc package of R, and for the haplotype analysis we used the package Haplo.stat. Finally, the significant genotypes were introduced in the PK model using 2 selection methods: a selection method from a full model using Wald tests, and forward inclusion method using the log-likelihood ratio test.
Results: The data were best fit with a model with 3 compartments for irinotecan, 2 compartments for SN38 the active metabolite, and a one compartment for the inactive metabolites (SN38G, APC and NPC), with a linear elimination in each case. We found significant association between several SNPs located abroad the promoter of NR1I2 and distribution volume of the central compartment for irinotecan both with single locus analysis and haplotypic approach. Furthermore we confirmed the pivotal role of UGT1A1*28 in the clearance of SN38.
Conclusions: Genetics polymorphisms of the promoter of NR1I2 are associated with the PK of irinotecan. Our data demonstrate that genetic variations of the transcriptional regulators of genes involved in the metabolism of drugs can impact the pharmacokinetic variability and suggest that this should take into account in adaptative dosing strategies.
Reference: PAGE 22 () Abstr 2658 [www.page-meeting.org/?abstract=2658]
Poster: Oncology