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 clinically more relevant than a singly measured nadir count. In order to identify factors associated with neutropenic fever, a mechanistic pharmacodynamic model with two compartments corresponding to leukocytes in bone marrow and peripheral blood was applied to describe the time course of leukopenia, seventeen 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-dependent parameters, including the time period during which leukocyte counts remained below 2000/mu1 and the area between the curve for time versus leukocyte counts and the line of a leukocyte count of 2000/mul (A<2000), were calculated 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 between age and the sensitivity parameter of the pharmacodynamic model was observed (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 pharmacokinetic parameter or the leukocyte nadir count. Febrile episodes were better associated with the time course of leukopenia than the singly measured nadir count, and the pharmacodynamic model presents a novel platform to analyze the entire time course of leukopenia.