Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats

Aim: To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats. Methods: Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated Results: A one-compartment model with non-lineal elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic E-max-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses. Conclusion: Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However; no schedule dependence was indicated for the schedules used in the study.