Abstract
The pharmacokinetics (PK) (absorption, distribution, metabolism, excretion) of peginesatide, a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA), was evaluated in rats. The PK profile was evaluated at 0.1–5 mg·kg−1 IV using unlabeled or [14C]-labeled peginesatide. Mass balance, tissue distribution and metabolism were evaluated following IV administration of 5 mg·kg−1 [14C]-peginesatide, with tissue distribution also evaluated by quantitative whole-body autoradiography (QWBA) following an IV dose of 17 mg·kg−1 [14C]-peginesatide.Plasma clearance was slow and elimination was biphasic with unchanged peginesatide representing >90% of the total radioactivity of the total radioactive exposure. Slow uptake of the radiolabeled compound from the vascular compartment into the tissues was observed.Biodistribution to bone marrow and extramedullary hematopoietic sites, and to highly vascularized lymphatic and excretory tissues occurred.A predominant degradation event to occur in vivo was the loss of one PEG chain from the branched PEG moiety to generate mono-PEG.Renal excretion was the primary mechanism (41%) of elimination, with parent molecule (67%) the major moiety excreted.In conclusion, elimination of [14C]-peginesatide-derived radioactivity was extended, retention preferentially occurred at sites of erythropoiesis (bone marrow), and urinary excretion was the primary elimination route.
Highlights
Erythropoietin (EPO) is a glycoprotein hormone synthesized by the kidney in response to hypoxia that regulates the proliferation, differentiation, and survival of erythroid progenitor cells (Krantz 1991)
Pharmacokinetics Pharmacokinetics were evaluated in rats following a single IV dose of peginesatide at 0.1, 0.5, and 5 mg·kg−1 (Figure 2, Table 1)
The studies and results described provide a comprehensive delineation of the peginesatide absorption, distribution, metabolism and excretion profile in the rat
Summary
Erythropoietin (EPO) is a glycoprotein hormone synthesized by the kidney in response to hypoxia that regulates the proliferation, differentiation, and survival of erythroid progenitor cells (Krantz 1991). The etiopathology of chronic kidney disease (CKD)-associated anemia is related to inadequate generation of erythropoietin by the diseased kidney. Recombinant human erythropoietin and its protein variants are used clinically for the correction of anemia secondary to CKD (Jelkmann 2008). Administration of an erythropoiesisstimulating agent (ESA) restores the appropriate stimulatory signal to erythroid progenitor cells located within the bone marrow, thereby treating the anemia, reducing the incidence of secondary sequelae, and notably reducing the requirement for blood transfusions. Peginesatide (formerly known as HematideTM) is a synthetic, PEGylated, investigational, peptide-based ESA that has an amino acid sequence unrelated to endogenous EPO (Fan et al 2006) and is currently being developed in the United States for the treatment of anemia due to CKD in patients on dialysis.
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