title: Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients.
abstract: OBJECTIVE
  The aims of the study were (a) to characterise the pharmacokinetics (PK), including inter-individual variability (IIV) and inter-occasion variability (IOV) as well as covariate relationships and (b) to characterise the relationship between the PK and the haematological toxicity of the component drugs of the fluorouracil (5-FU)-epirubicin (EPI)-cyclophosphamide (CP) regimen in breast cancer patients.
  
  
  METHODS
  Data from 140 breast cancer patients, either within one of different studies or in routine clinical management, were included in the analyses. The patients were all treated with the fluorouracil-epirubicin-cyclophosphamide (FEC) regimen every third week for 3-12 courses, either in standard doses, i.e. 600/60/600 mg/m(2) of 5-FU, EPI and CP, respectively, or according to a dose escalation/reduction protocol (tailored dosing). PK data were available from 84 of the patients, whereas time-courses of haematological toxicity were available from 87 patients. The data analysis was carried out using mixed effects models within the NONMEM program.
  
  
  RESULTS
  The PK of 5-FU, EPI and 4-hydroxy-cyclophosphamide (4-OHCP), the active metabolite of CP, were described with a one-compartment model with saturable elimination, a three-compartment linear model and a two-compartment linear model, respectively. No clinical significant correlation was found between PK across drugs. The unexplained variability in clearance was found to be less within patients, between courses (inter-occasion variability, IOV) than between patients (inter-individual variability, IIV) for EPI and 5-FU. For 4-OHCP, however, the IIV diminished by approximately 45% when significant covariates were included and the final population model predicts an IIV that is equal to IOV. Significant covariates for elimination capacity parameters were serum albumin (5-FU, EPI and 4-OHCP), creatinine clearance (5-FU), bilirubin (EPI) and body surface area (BSA) (4-OHCP). Elimination capacity of 5-FU and EPI was not related to BSA and for none of the studied drugs did body weight explain the PK variability. The time-course of haematological toxicity after treatment was well described by a semi-physiological model that assumes additive haematological toxicity between CP and EPI with negligible contribution from 5-FU. The influence of G-CSF could be incorporated into the model in a mechanistic manner as shortening the maturation time to 43% of the normal duration and increasing the mitotic activity to 269% of normal activity.
  
  
  CONCLUSIONS
  The models presented describe the dose-concentration-toxicity relationships for the FEC therapy and may provide a basis for implementation and comparison of different individualisation strategies based on covariates, therapeutic drug monitoring and/or pharmacodynamic (PD) feedback. The PD model extends on previous semi-mechanistic models in that it also takes G-CSF administration into account.
authors.affiliation: Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden. marie.sandstrom@astrazeneca.com
authors.forename: M
authors.initials: M
authors.lastname: Sandström
authors.forename: H
authors.initials: H
authors.lastname: Lindman
authors.forename: P
authors.initials: P
authors.lastname: Nygren
authors.forename: M
authors.initials: M
authors.lastname: Johansson
authors.forename: J
authors.initials: J
authors.lastname: Bergh
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil