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

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