Nastja Lunar1,2, Marie-Christine Etienne-Grimaldi3,4, Pauline Macaire1,2, Fabienne Thomas4,5,6, Florence Dalenc5,6, Jean-Marc Ferrero3, Xavier Pivot7, Gérard Milano3,4, Bernard Royer4,8,9, Antonin Schmitt10,11,12. 1. Pharmacy Department, Centre Georges-François Leclerc, 1 rue Pr Marion, 21079, Dijon Cedex, France. 2. INSERM U1231, University of Burgundy Franche-Comté, Dijon, France. 3. Centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189, Nice cedex 2, France. 4. Groupe de Pharmacologie Clinique & Oncologique (GPCO)-Unicancer, 101 rue de Tolbiac, 75013, Paris, France. 5. ICR, IUCT-Oncopole, Toulouse, France. 6. Université de Toulouse, CRCT, Inserm UMR1037, 31000, Toulouse, France. 7. Service Oncologie Médicale, CHU Jean-Minjoz, 3, boulevard Alexandre-Fleming, 25030, Besançon, France. 8. Laboratoire de Pharmacologie Clinique, CHU Jean-Minjoz, 3, boulevard Alexandre-Fleming, 25030, Besançon, France. 9. INSERM, EFS BFC, UMR1098, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Université Bourgogne Franche-Comté, 25000, Besançon, France. 10. Pharmacy Department, Centre Georges-François Leclerc, 1 rue Pr Marion, 21079, Dijon Cedex, France. antonin.schmitt@u-bourgogne.fr. 11. INSERM U1231, University of Burgundy Franche-Comté, Dijon, France. antonin.schmitt@u-bourgogne.fr. 12. Groupe de Pharmacologie Clinique & Oncologique (GPCO)-Unicancer, 101 rue de Tolbiac, 75013, Paris, France. antonin.schmitt@u-bourgogne.fr.
Abstract
PURPOSE: The present study was performed to examine relationships between systemic exposure of capecitabine metabolites (5-FU, 5'-DFCR and 5'-DFUR) and toxicity or clinical response in patients with metastatic breast cancer. METHODS: A population pharmacokinetic model for capecitabine and its three metabolites was built. Typical parameter values, characteristics of random distributions, associated with parameters, and covariates impact were estimated. Area under the curve (AUC) were computed for 5-FU and compared with grades of toxicity. Pharmacokinetic modeling was based on data collected on the first treatment cycle. Toxicity was assessed on the two first treatment cycles. RESULTS: The study was conducted in 43 patients. The population pharmacokinetic model (a one-compartment model per compound) was able to capture the very complex absorption process of capecitabine. Statistically significant covariates were cytidine deaminase, alkaline phosphatase and dihydrouracilemia (UH2)/uracilemia (U) ratio. UH2/U ratio was the most significant covariate on 5-FU elimination and CDA on the transformation of 5'-DFCR in 5'-DFUR. A trend was observed between 5-FU AUC and thrombopenia toxicity grades, but not with other toxicities. Best clinical response was not linked to systemic exposure of capecitabine metabolites. CONCLUSION: In our study, we propose a model able to describe, meanwhile, and its main metabolites, with a complex absorption process and inclusion of enzyme activity covariates such as CDA and UH2/U ratio. Trial registration Eudract 2008-004136-20, 2008/11/26.
PURPOSE: The present study was performed to examine relationships between systemic exposure of capecitabine metabolites (5-FU, 5'-DFCR and 5'-DFUR) and toxicity or clinical response in patients with metastatic breast cancer. METHODS: A population pharmacokinetic model for capecitabine and its three metabolites was built. Typical parameter values, characteristics of random distributions, associated with parameters, and covariates impact were estimated. Area under the curve (AUC) were computed for 5-FU and compared with grades of toxicity. Pharmacokinetic modeling was based on data collected on the first treatment cycle. Toxicity was assessed on the two first treatment cycles. RESULTS: The study was conducted in 43 patients. The population pharmacokinetic model (a one-compartment model per compound) was able to capture the very complex absorption process of capecitabine. Statistically significant covariates were cytidine deaminase, alkaline phosphatase and dihydrouracilemia (UH2)/uracilemia (U) ratio. UH2/U ratio was the most significant covariate on 5-FU elimination and CDA on the transformation of 5'-DFCR in 5'-DFUR. A trend was observed between 5-FU AUC and thrombopenia toxicity grades, but not with other toxicities. Best clinical response was not linked to systemic exposure of capecitabine metabolites. CONCLUSION: In our study, we propose a model able to describe, meanwhile, and its main metabolites, with a complex absorption process and inclusion of enzyme activity covariates such as CDA and UH2/U ratio. Trial registration Eudract 2008-004136-20, 2008/11/26.
Entities:
Keywords:
Breast cancer; Capecitabine; Modelling; PD; PK; Toxicity
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