Le. Friberg et al., Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats, J PHARM EXP, 295(2), 2000, pp. 734-740
Citations number
41
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.