title: Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.
abstract: OBJECTIVE
  The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients.
  
  
  METHODS
  Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM.
  
  
  RESULTS
  The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found.
  
  
  CONCLUSIONS
  Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.
authors.affiliation: Department of Pharmacy, University Hospital, Uppsala University, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Sandström
authors.forename: A
authors.initials: A
authors.lastname: Freijs
authors.forename: R
authors.initials: R
authors.lastname: Larsson
authors.forename: P
authors.initials: P
authors.lastname: Nygren
authors.forename: M L
authors.initials: ML
authors.lastname: Fjällskog
authors.forename: J
authors.initials: J
authors.lastname: Bergh
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008875:Middle Aged
chemical_list: C012358:4-hydroxycyclophosphamide; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil