Laure Deyme1, Dominique Barbolosi2, Litaty Céphanoée Mbatchi3,4, Nicole Tubiana-Mathieu5, Marc Ychou6, Alexandre Evrard3,4, Florence Gattacceca2. 1. SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. laure.deyme@gmail.com. 2. SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. 3. Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France. 4. IRCM, Inserm U1194, Université de Montpellier, Montpellier, France. 5. Centre Hospitalier Universitaire de Limoges, Limoges, France. 6. Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Abstract
PURPOSE: The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS: A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS: A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION: To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00559676.
PURPOSE: The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancerpatients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS: A multicenter study including 109 metastatic colorectal cancerpatients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS: A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION: To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00559676.
Entities:
Keywords:
CPT-11; FOLFIRI; FOLFIRINOX; Nonlinear mixed effect modelling; Population pharmacokinetics
Authors: R H Mathijssen; R J van Alphen; J Verweij; W J Loos; K Nooter; G Stoter; A Sparreboom Journal: Clin Cancer Res Date: 2001-08 Impact factor: 12.531
Authors: Ron H J Mathijssen; Sharon Marsh; Mats O Karlsson; Rujia Xie; Sharyn D Baker; Jaap Verweij; Alex Sparreboom; Howard L McLeod Journal: Clin Cancer Res Date: 2003-08-15 Impact factor: 12.531