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. (April 2014)

• Record Type: Journal Article
• Authors: Andrews, Dina A.; Boren, Babette M.; Turk, James R.; Boyce, Rogely W.; He, Yudong D.; Hamadeh, Hisham K.; Mytych, Daniel T.; Barger, Troy E.; Salimi-Moosavi, Hossein; Sloey, Bethlyn; Elliott, Steve; McElroy, Patricia; Sinclair, Angus M.; Shimamoto, Grant; Pyrah, Ian T. G.; Lightfoot-Dunn, Ruth M.
• Is Part Of: Toxicologic pathology. Volume 42:Number 3(2014:Apr.)
• Page Start: 524
• Page End: 539
• Publication Date: 2014-04
• Subjects: erythropoiesis -- rat -- pathology -- polycythemia -- thrombosis -- iron -- reticulocytes.; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623313486319
• Languages: English
• ISSNs: 0192-6233

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.