Lena E. Friberg and Mats O. Karlsson
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Sweden
Aim: To develop a pharmacokinetic-pharmacodynamic model for leukocyte toxicity after administration of 5-fluorouracil and epirubicin in combination in rats.
Methods: Different dose levels of 5-fluorouracil and epirubicin were injected as single drugs or in combination to rats. NONMEM was used to develop pharmacokinetic models and to apply a relatively simple semi-physiological model for the leukocyte data. Simulations were performed to evaluate the type of interaction at different dose levels and times.
Results: The pharmacokinetics of 5-fluorouracil could be described with a one-compartment model with capacity-limited elimination and a three-compartment model described the epirubicin concentration data. No pharmacokinetic interaction between the two drugs was found. The semi-physiological model included a proliferative compartment, three transit compartments and a compartment for the observed, circulating leukocytes. A feedback on the proliferation from the circulating cells was incorporated. Linear concentration-effect models on the proliferation described the effect of the drugs when used in single administration and the best combination model just added the linear effects of the two drugs. However, although the drug effect is linear and additive at the level of the proliferative compartment, it may be non-linear and non-additive at the level of the circulating leukocytes.
Conclusion: This semi-physiological model could qualitatively and quantitatively describe the pharmacodynamic interaction on circulating leukocytes after administration of 5-fluorouracil and epirubicin in combination.
Reference: PAGE 10 (2001) Abstr 272 [www.page-meeting.org/?abstract=272]
Poster: poster