Nonclinical Safety Assessment of a Synthetic Peptide Thrombopoietin Agonist: Effects on Platelets, Bone Homeostasis, and Immunogenicity and the Implications for Clinical Safety Monitoring of Adverse Bone Effects

Elaine Knight, Gary Eichenbaum, Verna Hillsamer, Tony Greway, Alfred Tonelli, Helen Han-Hsu, Cindy Zakszewski, Edward Yurkow, Umesh Shukla, David End, Calvert Louden

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

RWJ-800088 is a novel, potent polyethylene glycol (PEG)-conjugated thrombopoietin (TPO) mimetic that increases platelet levels and protects against thrombocytopenia. A nonclinical safety program was customized for this peptide that takes into account its protein-like structure, synthetic chemical nature, agonist pharmacologic activity, and mode of administration. In repeat-dose toxicity studies, the salient findings were dose-related increases in circulating platelet counts, mean platelet volume, and megakaryocytes in the bone marrow with no antibody formation. Reversible myelofibrosis and hyperostosis were observed in rats, but not dogs, when the circulating platelet levels exceeded 3× those of vehicle controls. The bone effects were due to the exaggerated pharmacologic effect and excessive stimulation and elevation of megakaryocytes by TPO, which results in intramedullary proliferation of fibroblasts and mesenchymal cells followed by osseous metaplasia. These findings support the use of platelet elevations of >3× as a stopping criterion to prevent potential adverse bone-related effects in humans.

Original languageEnglish (US)
Pages (from-to)385-404
Number of pages20
JournalInternational Journal of Toxicology
Volume30
Issue number4
DOIs
StatePublished - Aug 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Toxicology

Keywords

  • PEGylation
  • hyperostosis
  • myelofibrosis
  • nonclinical safety
  • platelets
  • thrombocytopenia
  • thrombopoietin agonist

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