Population Pharmacokinetic Modelling of Filgrastim in Healthy Adults following Intravenous and Subcutaneous Administrations

Abstract

Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM. The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.