Population Pharmacokinetic–Pharmacodynamic Modeling of Filgrastim (r-metHuG-CSF) in Healthy Volunteers

Abstract

The pharmacokinetic–pharmacodynamic (PK–PD) relationship of the granulopoietic effects of Filgrastim in healthy volunteers was characterized via a population approach. Healthy male volunteers were enrolled into a four-way crossover clinical trial. Subjects received four single doses of Filgrastim (375 and 750 μg iv and sc) with an intervening washout period of 7 days. Serum concentrations of Filgrastim were determined using an enzyme-linked immunosorbent assay. Absolute neutrophil count (ANC) was determined. Data analysis was performed using mixed-effects modeling as implemented in the NONMEM software package. The final PKPD model incorporates a two-compartment PK model with bisegmental absorption from the sc site, first-order and saturable elimination pathways, and an indirect PD model. A sigmoidal E_max model for the stimulation of ANC input rate k_in) was superior to the conventional E_max model (${\bar X}$ ±SE: E_max=12.7 ± 1.7; EC50=4.72 ± 0.72 ng/ml; Hill=1.34 ± 0.19). In addition, a time-variant scaling factor for ANC observations was introduced to account for the early transient depression of ANC after Filgrastim administration. The absolute bioavailability of subcutaneously administered Filgrastim was estimated to be 0.619±0.058 and 0.717±0.028 for 375 μg and 750 μg sc doses, respectively. The time profiles of concentration and ANC, as well as the concentration∼ANC relationship of Filgrastim in healthy volunteers were well described by the developed population PK–PD model.