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

作者：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

来源：Toxicologic Pathology, 2014, 42(3): 524-539.

DOI：10.1177/0192623313486319

• erythropoiesis
• rat
• pathology
• polycythemia
• thrombosis
• iron
• reticulocytes

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.

• 出版日期2014-4