Pharmacodynamic modeling of the entire time course of leukopenia after a 3-hour infusion of paclitaxel

The entire time course of leukopenia after anticancer treatment is clinical ly more relevant than a singly measured nadir count. In order to identify f actors associated with neutropenic fever, a mechanistic pharmacodynamic mod el with two compartments corresponding to leukocytes in bone marrow and per ipheral blood was applied to describe the time course of leukopenia, sevent een patients with breast cancer were treated with 210 mg/m(2) of paclitaxel infused over 3 h as a single agent in a phase II. study, Adequate fitting of the time course of leukopenia was achieved in all patients, and time-dep endent parameters, including the time period during which leukocyte counts remained below 2000/mu1 and the area between the curve for time versus leuk ocyte counts and the line of a leukocyte count of 2000/mul (A<2000), were c alculated in each patient. Leukopenia was not significantly correlated with pharmacokinetic parameters, including time above a threshold concentration or the area under the time-concentration curve. A negative correlation bet ween age and the sensitivity parameter of the pharmacodynamic model was obs erved (r(2)=0.21, P=0.07), Patients who experienced neutropenic fever had a larger A<2000 than patients who did not experience fever (4512 vs. 6 days/ mul, P=0.05), but fever was not significantly related to any pharmacokineti c parameter or the leukocyte nadir count. Febrile episodes were better asso ciated with the time course of leukopenia than the singly measured nadir co unt, and the pharmacodynamic model presents a novel platform to analyze the entire time course of leukopenia.