Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats

Models of leukopenia after chemotherapy are mainly empirical. To increase t he derived models' potential of mechanistic understanding and extrapolation , more physiologically based models are being developed. To date, presented models cannot characterize the often-observed rebound of leukocytes. There fore, a model able to describe the transient decrease and rebound in leukoc ytes was developed. Three different dosing regimens of 5-fluorouracil were given to rats. One group received a single dose of 127 mg/kg. The other two groups received two and three injections of 63 mg/kg and 49 mg/kg, respect ively, with a 2-day interval. Leukocyte counts were followed for 23 to 25 d ays after the first dose. Plasma concentrations were determined by high-per formance liquid chromatography. Population pharmacokinetic and pharmacodyna mic models were developed using NONMEM. 5-Fluorouracil showed one-compartme nt disposition with capacity-limited elimination. The 49-mg/kg dose injecte d on three occasions produced the lowest leukocyte count (28% of baseline) and the most prominent rebound of the schedules, despite the fact that the fractionated regimens produced only 52 to 56% of the area under the concent ration-time curve from time 0 to infinity in the single-dose group. The fin al semiphysiological model included two 5-fluorouracil-sensitive and two-in sensitive transit compartments as well as a compartment of circulating leuk ocytes. Second order rate constants from the transit compartments and a neg ative feedback from the circulating leukocytes to the input of the first se nsitive compartment characterized the pronounced changes in leukocyte count s. A posterior predictive check as well as predictions into a new data set showed that our model could well predict the schedule-dependent leukopenic effects of 5-fluorouracil.