Population pharmacokinetic analysis of GX-E2, a novel erythropoiesis stimulating agent, in healthy male subjects

Abstract

Introduction: GX-E2 is a novel erythropoiesis stimulating agent which is human erythropoietin (EPO) fused with Fc region of the antibody. The pharmacokinetic (PK)/pharmacodynamic (PD) properties following a single intravenous (IV) and subcutaneous (SC) injection of GX-E2 have been revealed by the noncompartmental analysis of preclinical and clinical study. The SC injection of GX-E2 presented the extended mean residence time and duration of action than currently marketed EPO. The objective of this study was to characterize the PK properties following a sin-gle IV and SC injection of GX-E2 by developing population PK models. Methods: For the model development, data were pooled from two phase I clinical trials. Two different approaches were applied for describing the disposition of GX-E2: Simple disposition model in which describes the model with Michaelis-Menten enzyme kinetics were tested. Target-mediated drug disposition (TMDD) model was tested for mechanistic understanding of PK properties. Each model was numerically and graphically diagnosed to select the final model. Visual predictive check was per-formed to validate the predictive performance of the final model. Results: A total of 1084 serum GX-E2 concentrations were obtained from 72 sub-jects. The PK properties of GX-E2 were well described by the 2-compartment model with first-order absorption. Both Michaelis-Menten enzyme kinetic model and TMDD model could adequately explain the characteristic PK profiles of GX-E2. An acceptable predictive performance of each final model was validated by the visual predictive check. Approximately 50 – 70% of the SC injected dose was predicted to be absorbed into the systemic circulation with the first-order absorption constant of 0.003 h-1. From the estimated clearances of free-form and bound form, majority of injected GX-E2 are predicted to be eliminated as a bound form. Conclusion: This study first described the PK of GX-E2 by developing population PK models. Both simple disposition model and TMDD model were fitted well with the observed data, how-ever, TMDD model had advantage in reflecting mechanistic aspects of drug. Further assessments of absorption mechanism and inclusion of PD factors in current model will enable to assess the further in-depth understanding of GX-E2 PK profile.