PHARMACOKINETICS AND PHARMACODYNAMICS OF RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR (RHG-CSF) FOLLOWING INTRANASAL ADMINISTRATION IN RABBITS

The objective of this study was to evaluate the pharmacokinetics and p harmacodynamics of G-CSF as well as their relationship following intra nasal (i.n.) administration of aqueous rhG-CSF preparations with or wi thout additives. In order to achieve a better understanding of the dos age regimen and the effectiveness of intranasally administered rhG-CSF in inducing leukopoiesis, we investigated rhG-CSF absorption and bloo d leukocyte dynamics with respect to dose in rabbits. RhG-CSF could be absorbed through the nasal cavity of rabbits when rhG-CSF aqueous pre parations, especially those containing alpha-cyclodextrin (alpha-CyD) were intranasally administered. We found that serum G-CSF levels and t he total count of leukocytes in peripheral blood (total blood leukocyt e count) showed a dose-dependent increase with rhG-CSF. The area under the serum G-CSF concentration-time curve (AUG, a pharmacokinetic para meter) and the area under the increased total blood leukocyte count-ti me curve (AUC, a pharmacodynamic parameter) increased with increase of dose of rhG-CSF administered intranasally. Good agreement was observe d between log AUC and AUL; thus, it is concluded that an increase of A UC leads to an increase in effectiveness of rhG-CSF in inducing leukop oiesis in rabbits. A novel rhG-CSF delivery system in the form of i.n. administration of rhG-CSF was thus achieved.