Anaemia

Introduction and Aims: Peginesatide is a PEGylated, investigational, peptide-based erythropoiesis stimulating agent that is designed to specifically stimulate the EPOR and is currently being developed for the treatment of anemia of chronic kidney disease in dialysis patients.The peginesatide peptide has a unique structure with no sequence similarity to erythropoietin.This study was conducted across species to evaluate the pharmacokinetics (PK), to define the extent of systemic exposure, to characterize erythropoietic activity in vivo, and to examine a possible mechanism of clearance.Methods: Mouse, rat, rabbit, dog, and monkey were given a single IV dose of 0.05-2 mg/kg peginesatide.Blood samples were obtained for PK analysis and to evaluate erythropoietic response.Binding of peginesatide to the EPOR of each species was quantified using a radioligand competition binding assay.Results: Elimination of peginesatide from the plasma exhibited a biphasic pattern characterized by a rapid initial phase and a prolonged terminal phase.The dose-dependent half-lives ranged from 19.9 hours in the rat to 73.7 hours in dog.The volume of distribution approximated the plasma volume in each species, suggesting that peginesatide is confined primarily to the vascular compartment.Peginesatide was pharmacologically active in mice, rats, rabbits, and monkeys.Administration resulted in consistent dose-dependent increases in BFU-E, reticulocytes, hemoglobin, and red blood cells.Surprisingly, peginesatide was not active in the dog despite higher per-dose exposure than other species.Quantification of EPOR binding demonstrated that peginesatide binds to the mouse and rat EPOR with high affinity (IC50s of 101 and 38 pM, respectively).Although the dog EPOR is highly homologous with the EPOR from other species, peginesatide did not bind.A comparison of sequences revealed that methionine 150 of the EPOR, an amino acid previously shown to be involved in binding of peginesatide-related peptides, is conserved in all tested species except the dog.Mutation of the valine at this position in the dog EPOR to methionine allowed peginesatide to bind the mutant dog EPOR with high affinity (IC 50 97 pM).Conclusions: A similar PK and erythropoietic response profile for peginesatide was observed across all species tested, except the dog.Peginesatide has a longer half-life and greater systemic exposure in the dog.This observation, taken together with the lack of peginesatide binding to the dog EPOR, suggests that clearance of peginesatide may be mediated in part by EPOR.

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