title: Dose-related differences in the pharmacodynamic and toxicologic response to a novel hyperglycosylated analog of recombinant human erythropoietin in Sprague-Dawley rats with similarly high hematocrit.
abstract: We recently reported results that erythropoiesis-stimulating agent (ESA)-related thrombotic toxicities in preclinical species were not solely dependent on a high hematocrit (HCT) but also associated with increased ESA dose level, dose frequency, and dosing duration. In this article, we conclude that sequelae of an increased magnitude of ESA-stimulated erythropoiesis potentially contributed to thrombosis in the highest ESA dose groups. The results were obtained from two investigative studies we conducted in Sprague-Dawley rats administered a low (no thrombotic toxicities) or high (with thrombotic toxicities) dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114), 3 times weekly for up to 9 days or for 1 month. Despite similarly increased HCT at both dose levels, animals in the high-dose group had an increased magnitude of erythropoiesis measured by spleen weights, splenic erythropoiesis, and circulating reticulocytes. Resulting prothrombotic risk factors identified predominantly or uniquely in the high-dose group were higher numbers of immature reticulocytes and nucleated red blood cells in circulation, severe functional iron deficiency, and increased intravascular destruction of iron-deficient reticulocyte/red blood cells. No thrombotic events were detected in rats dosed up to 9 days suggesting a sustained high HCT is a requisite cofactor for development of ESA-related thrombotic toxicities.
authors.affiliation: 1Comparative Biology Safety Sciences, Pathology, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Dina A
authors.initials: DA
authors.lastname: Andrews
authors.forename: Babette M
authors.initials: BM
authors.lastname: Boren
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.forename: Rogely W
authors.initials: RW
authors.lastname: Boyce
authors.forename: Yudong D
authors.initials: YD
authors.lastname: He
authors.forename: Hisham K
authors.initials: HK
authors.lastname: Hamadeh
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Mytych
authors.forename: Troy E
authors.initials: TE
authors.lastname: Barger
authors.forename: Hossein
authors.initials: H
authors.lastname: Salimi-Moosavi
authors.forename: Bethlyn
authors.initials: B
authors.lastname: Sloey
authors.forename: Steve
authors.initials: S
authors.lastname: Elliott
authors.forename: Patricia
authors.initials: P
authors.lastname: McElroy
authors.forename: Angus M
authors.initials: AM
authors.lastname: Sinclair
authors.forename: Grant
authors.initials: G
authors.lastname: Shimamoto
authors.forename: Ian T G
authors.initials: IT
authors.lastname: Pyrah
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Lightfoot-Dunn
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001792:Blood Platelets; D004912:Erythrocytes; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D006400:Hematocrit; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D008297:Male; D011086:Polycythemia; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D012156:Reticulocytes
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin; D007501:Iron
keywords: erythropoiesis; iron; pathology; polycythemia; rat; reticulocytes.; thrombosis