CLINICAL-PHARMACOLOGY OF FILGRASTIM FOLLOWING HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS BONE-MARROW TRANSPLANTATION

We evaluated the pharmacokinetics and pharmacodynamics of filgrastim d uring a Phase I study of this cytokine following high-dose chemotherap y and autologous bone marrow transplantation. Serum granulocyte colony -stimulating factor concentrations were determined by ELISA in 21 pati ents receiving 14-day continuous i,v, filgrastim infusions and 10 pati ents receiving daily 4-h infusions, Models were developed for filgrast im systemic clearance (Cls) by incorporation of receptor-binding theor y. Mean plasma half-life (t(1/2)) in the 4-h infusion group was 197 mi n, and the volume of distribution approximated plasma volume, WBC coun ts transiently fell, then rebounded immediately postinfusion, which co rrelated with a delay in the disappearance of serum granulocyte colony -stimulating factor. The effect of WBC concentrations on filgrastim Cl s was determined in patients receiving continuous infusions by segrega tion of study periods based on the presence of severe neutropenia. Cle arance increased in all 14 patients receiving doses of 4-32 mu g/kg/da y during WBC recovery. The effect of WBCs on Cls was described by a di fferential 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 tr ansplantation may be suboptimal.