Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin

Abstract

We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 highdose group, but not in lower dose groups with a similar high HCT.

Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor

“…41 However, some of the non-neoplastic toxicologic effects of daprodustat may have other contributory mechanisms, as it has been reported that some ESA-related toxicities are not solely dependent upon increased Hct. 56 The reduction in EPO mRNA expression observed in daprodustat-treated rat and mouse kidneys sampled at week 26 of dosing was surprising, given the dose-dependent increases observed in liver EPO mRNA expression. The mechanism behind these differing EPO expression patterns between liver and kidney are not understood.…”

“…41 However, some of the non-neoplastic toxicologic effects of daprodustat may have other contributory mechanisms, as it has been reported that some ESA-related toxicities are not solely dependent upon increased Hct. 56…”