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

Author:

Andrews Dina A.1,Boren Babette M.2,Turk James R.1,Boyce Rogely W.1,He Yudong D.3,Hamadeh Hisham K.4,Mytych Daniel T.5,Barger Troy E.5,Salimi-Moosavi Hossein6,Sloey Bethlyn6,Elliott Steve7,McElroy Patricia7,Sinclair Angus M.7,Shimamoto Grant8,Pyrah Ian T. G.9,Lightfoot-Dunn Ruth M.9

Affiliation:

1. Comparative Biology Safety Sciences, Pathology, Amgen Inc., Thousand Oaks, California, USA

2. Comparative Biology Safety Sciences, Toxicology Sciences, Amgen Inc., Thousand Oaks, California, USA

3. Comparative Biology and Safety Sciences, Discovery Toxicology, Amgen Inc., Seattle, Washington, USA

4. Comparative Biology and Safety Sciences, Discovery Toxicology, Amgen Inc., Thousand Oaks, California, USA

5. Medical Sciences, Clinical Immunology, Amgen Inc., Thousand Oaks, California, USA

6. Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA

7. Discovery Research, Oncology Research, Amgen Inc., Thousand Oaks, California, USA

8. Therapeutic Discovery, Biologic Optimization, Amgen Inc., Thousand Oaks, California, USA

9. Comparative Biology Safety Sciences, Executive and Operations, Amgen, Inc., Thousand Oaks, California, USA

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.

Publisher

SAGE Publications

Subject

Cell Biology,Toxicology,Molecular Biology,Pathology and Forensic Medicine

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