Clinical pharmacology of filgrastim following high-dose chemotherapy and autologous bone marrow transplantation

We evaluated the pharmacokinetics and pharmacodynamics of filgrastim during a Phase I study of this cytokine following high-dose chemotherapy and autologous bone marrow transplantation. Serum granulocyte colony-stimulating factor concentrations were determined by ELISA in 21 patients receiving 14-day continuous i,v, filgrastim infusions and 10 patients receiving daily 4-h infusions, Models were developed for filgrastim systemic clearance (Cls) by incorporation of receptor-binding theory. Mean plasma half-life (t(1/2)) in the 4-h infusion group was 197 min, and the volume of distribution approximated plasma volume, WBC counts transiently fell, then rebounded immediately postinfusion, which correlated with a delay in the disappearance of serum granulocyte colony-stimulating factor. The effect of WBC concentrations on filgrastim Cls was determined in patients receiving continuous infusions by segregation of study periods based on the presence of severe neutropenia. Clearance increased in all 14 patients receiving doses of 4-32 mu g/kg/day during WBC recovery. The effect of WBCs on Cls was described by a differential equation that included a static component and one component that varied with WBC concentration, These data suggest that currently used filgrastim dosing strategies following autologous bone marrow transplantation may be suboptimal.