Vol. 295, Issue 2, 734-740, November 2000

Semiphysiological Model for the Time Course of Leukocytes after Varying Schedules of 5-Fluorouracil in Rats¹

Lena E. Friberg, Agneta Freijs, Marie Sandström and Mats O. Karlsson

Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden

Models of leukopenia after chemotherapy are mainly empirical. To increase the 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. Therefore, a model able to describe the transient decrease and rebound in leukocytes 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, respectively, with a 2-day interval. Leukocyte counts were followed for 23 to 25 days after the first dose. Plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic and pharmacodynamic models were developed using NONMEM. 5-Fluorouracil showed one-compartment disposition with capacity-limited elimination. The 49-mg/kg dose injected 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 concentration-time curve from time 0 to infinity in the single-dose group. The final semiphysiological model included two 5-fluorouracil-sensitive and two -insensitive transit compartments as well as a compartment of circulating leukocytes. Second order rate constants from the transit compartments and a negative feedback from the circulating leukocytes to the input of the first sensitive compartment characterized the pronounced changes in leukocyte counts. 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.