Génotypage de l’UGT1A1*28 et dosage plasmatique de l’irinotécan et son métabolite actif (SN38) par HPLC-MS/MS en vue d’une adaptation posologique et prévention de sa toxicité dans le traitement du cancer colorectal métastatique

Abstract

Introduction Inter-individual variability in the pharmacokinetics of irinotecan (CPT-11) and its active metabolite SN-38 significantly influences the occurrence of toxicities in patients with metastatic colorectal cancer. The UGT1A1*28 polymorphism and total bilirubin are factors that modulate SN-38 clearance and the risk of toxicity. No Algerian study has evaluated the association between this genotype and plasma exposure to irinotecan and SN-38. Methods A prospective study was conducted in 83 patients with colorectal cancer. UGT1A1*28 genotyping was performed by qPCR. Plasma concentrations of CPT-11 and SN-38 were measured at 2 and 48 hours after infusion using HPLC-MS/MS. Correlations between genotype, bilirubin, metabolite exposure, and major clinical toxicities (diarrhea, neutropenia, nausea/vomiting) were analyzed. Results The observed genotype frequencies were 38.6 % for *1/*1, 49.4 % for *1/*28, and 12 % for *28/*28, consistent with Mediterranean and North African profiles. The *28/*28 genotype did not affect CPT-11 concentrations but was associated with significantly increased and prolonged exposure to SN-38. Pre-treatment total bilirubin correlated positively with late SN-38 exposure. The risk of severe diarrhea was higher in homozygous *28/*28 patients, whereas associations with neutropenia and nausea/vomiting were more limited..