Sandström M (1), Lindman H (2) , Nygren P (2), and Karlsson MO (1)
(1) Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden. (2) Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden.
Objectives: The aims of the study were (i) to characterise the pharmacokinetics (PK), including inter-individual and inter-occasion variability as well as covariate relationships and (ii) 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 were included in the analyses. The patients were all treated with the FEC regimen every third week for three to twelve courses, either in standard doses, i.e. 600/60/600 mg/m2 of 5-FU, EPI and CP, respectively, or according to a dose escalation/reduction protocol (tailored dosing). Pharmacokinetic 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 the IIV diminished by one half when significant covariates were included and the final population model predicts an IIV that is equal to IOV. 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 and increasing the mitotic 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 feedback. The pharmacodynamic model extends on previous semi-mechanistic models in that it also takes G-CSF administration into account.
Reference: PAGE 12 (2003) Abstr 454 [www.page-meeting.org/?abstract=454]
Poster: poster