Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.
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.
Sandström
M
M
Department of Pharmacy, University Hospital, Uppsala University, Sweden.
Freijs
A
A
Larsson
R
R
Nygren
P
P
Fjällskog
M L
ML
Bergh
J
J
Karlsson
M O
MO
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
C012358:4-hydroxycyclophosphamide; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil