title: Population pharmacokinetic analysis of 5-FU and 5-FDHU in colorectal cancer patients: search for biomarkers associated with gastro-intestinal toxicity.
abstract: OBJECTIVE
  The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5 fluoro-5,6- dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5- FDHU and toxicity following i.v. bolus administration has not been studied using the population pharmacokinetics approach.
  
  
  METHODS
  Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5- FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events.
  
  
  RESULTS
  A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the inter-compartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA-weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men.
  
  
  CONCLUSIONS
  A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women.
authors.affiliation: UMR-MD3, Aix-Marseille Univ, 13375 Marseille, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Woloch
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Hafedh
authors.initials: H
authors.lastname: Marouani
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Athanassios
authors.initials: A
authors.lastname: Iliadis
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009325:Nausea / Q000139:chemically induced; D012189:Retrospective Studies; D014839:Vomiting / Q000139:chemically induced
chemical_list: D015415:Biomarkers; C019389:5-fluorodihydrouracil; D005472:Fluorouracil