M. Sandström(1) , A. Freijs(1) , R. Larsson(2) , P. Nygren(3) , J. Bergh(3) , M-L. Fjällskog(3) , M.O. Karlsson(1) ,
Department of Biopharmaceutics and Pharmacokinetics, Uppsala
University, Sweden(1)
Division of Clinical Pharmacology(2) and Department of Oncology(3) ,
University Hospital,
Uppsala University, Sweden
Purpose
The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI),5-fluorouracil (5FU) and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients.
Patients and methods
Data from 21 women were collected over a total of 35 cycles. 5FU
(300-600mg/
) and CP (300- 600mg/
) were given as bolus
injections, whereas EPI (15-60mg/ 
) was given 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 5FU was 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 105mg/L/h and 27mg/L, respectively. EPI concentration-time profiles showed a triexponential decline with an average terminal half-life of 24h and a clearance of 59L/h. The elimination of 4-OHCP was monoexponential with an average half-life of 7h. The interindividual coefficient of variation in apparent clearance was 30%, 22%, and 41% for 5FU, EPI and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in clearance were 11%, 8% and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found.
Conclusion
Dose escalation to maximal tolerated dose, individualisation using therapeutic drug monitoring or attempts to find concentration-response relationships may be successful but requires that the exposure of all three drugs are considered simultaneously.