Population Pharmacokinetic-Pharmacodynamic Modeling of Granulocyte Colony-Stimulating Factor to Optimize Dosing and Timing for CD34<SUP>+</SUP> Cell Harvesting

Abstract

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood (PB) progenitor cells from bone marrow (BM) into circulation for PB stem cell transplantation (PBSCT). This study aimed to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model of filgrastim in healthy subjects to optimize PB CD34+ cell collection. Plasma filgrastim concentrations and CD34+ cell count data were obtained from a clinical study involving healthy Korean subjects. A total of 1378 plasma concentration measurements and 982 CD34+ cell count data collected from 53 subjects were used in the PK-PD model. Filgrastim PKs were adequately described by a one-compartment linear disposition model with an additional transit compartment for absorption. Log-transformed body weight was the only significant covariate affecting the volume of distribution and clearance. CD34+ cell mobilization was best captured by a modified Friberg model, assuming continual entry of proliferating BM stem cells into PB via a single transit compartment. Simulation results suggested that the 5 μg/kg twice-daily dosing regimen may yield higher CD34+ cell counts compared to the 10 μg/kg once-daily regimen for achieving target CD34+ cell counts of 20/μL and 50/μL. We successfully developed a robust PK-PD model of G-CSF that optimizes the yield of CD34+ cells during allogeneic PBSCT. This model can guide the efficient determination of optimal G-CSF dosing regimens and CD34+ cell harvesting strategies