PHARMACOKINETIC PHARMACODYNAMIC ANALYSIS OF NEUTROPHIL PROLIFERATION INDUCED BY RECOMBINANT GRANULOCYTE-COLONY-STIMULATING FACTOR (RHG-CSF)- COMPARISON BETWEEN INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION/

Pharmacological effect after intravenous (i.v.) or subcutaneous (s.c.) administration of human recombinant granulocyte colony stimulating fa ctor (rhG-CSP) was evaluated by using a physiologically based pharmaco kinetic/pharmacodynamic model. The increase of neutrophil counts in bl ood after s.c. administration of rhG-CSB (0.5-1.0 pg/kg) was larger th an that after i.v. administration of the same dose, while area under t he curves of plasma concentration of rhG-CSF after s.c. administration was smaller than that after i.v. administration (Azuma et al., J. Cli n. Therap. Med., 5, 1579-1603, 1989). Based on the pharmacokinetic/pha rmacodynamic model considering metabolic turnover of neutrophil in vis e, time course of absolute neutrophil counts in blood after either typ e of rhG-CSF administration to normal healthy volunteers was analyzed. The nonlinear relationship between the concentration of rhG-CSF and i n vitro activity for proliferation of neutrophil could be explained by the drug-receptor-effector ternary complex model. These in vivo and i n vitro models made it possible to understand the above-mentioned disc repancy of pharmacokinetic/pharmacodynamic behavior between i.v. and s .c. administration of rhG-CSF. Simulation of the neutrophil count-time profiles after repeated i.v. and s.c, dosing of rhG-CSF according to these models showed good agreement with the observed data. In order to obtain the rational dosage regimen of rhG-CSF from pharmacological an d economical points of view, a slow constant infusion method may be mo re useful than rapid infusion.