Population pharmacokinetic-pharmacodynamic modeling of Filgrastim (r-metHuG-CSF) in healthy volunteers

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the granulopoie tic effects of Filgrastim in healthy volunteers was characterized via a pop ulation approach. Healthy male volunteers were enrolled into a four-way cro ssover clinical trial. Subjects received four single doses of Filgrastim (3 75 and 750 mug iv and sc) with an intervening washout period of 7 days. Ser um concentrations of Filgrastim were determined using an enzyme-linked immu nosorbent assay. Absolute neutrophil count (ANC) was determined. Data analy sis was performed using mixed-effects modeling as implemented in the NONMEM software package. The final PKPD model incorporates a two-compartment PK m odel with bisegmental absorption from the sc site, first-order and saturabl e elimination pathways, and an indirect PD model. A sigmoidal E-max model f or the stimulation of ANC input rate (k(in)) was superior to the convention al E-max model ((x) over bar +/- 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 fact or for ANC observations was introduced to account for the early transient d epression of ANC after Filgrastim administration. The absolute bioavailabil ity of subcutaneously administered Filgrastim was estimated to be 0.619 +/- 0.058 and 0.717 +/- 0.028 for 375 mug and 750 mug sc doses, respectively. The time profiles of concentration and ANC, as well as the concentration-AN C relationship of Filgrastim in healthy volunteers were well described by t he developed population PK-PD model.