title: Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration.
abstract: Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.
authors: Affymax, Inc., Palo Alto, California, USA.
authors: Kathryn W
authors: KW
authors: Woodburn
authors: Kei-Lai
authors: KL
authors: Fong
authors: Susan D
authors: SD
authors: Wilson
authors: Steven
authors: S
authors: Sloneker
authors: Paul
authors: P
authors: Strzemienski
authors: Eric
authors: E
authors: Solon
authors: Yuu
authors: Y
authors: Moriya
authors: Yoshihiko
authors: Y
authors: Tagawa
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001682:Biological Availability; D001853:Bone Marrow / Q000000981:diagnostic imaging / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects; D006397:Hematinics / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011877:Radionuclide Imaging; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D006397:Hematinics; D010455:Peptides; C556270:peginesatide