title: 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.
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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ 08869, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Knight
authors.forename: Gary
authors.initials: G
authors.lastname: Eichenbaum
authors.forename: Verna
authors.initials: V
authors.lastname: Hillsamer
authors.forename: Tony
authors.initials: T
authors.lastname: Greway
authors.forename: Alfred
authors.initials: A
authors.lastname: Tonelli
authors.forename: Helen
authors.initials: H
authors.lastname: Han-Hsu
authors.forename: Cindy
authors.initials: C
authors.lastname: Zakszewski
authors.forename: Edward
authors.initials: E
authors.lastname: Yurkow
authors.forename: Umesh
authors.initials: U
authors.lastname: Shukla
authors.forename: David
authors.initials: D
authors.lastname: End
authors.forename: Calvert
authors.initials: C
authors.lastname: Louden
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006168:Guinea Pigs; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D015576:Hyperostosis / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects; D010455:Peptides / Q000276:immunology / Q000493:pharmacokinetics* / Q000633:toxicity; D055728:Primary Myelofibrosis / Q000473:pathology; D011817:Rabbits; D051381:Rats; D013921:Thrombocytopenia / Q000188:drug therapy; D018675:Toxicity Tests
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C539273:RWJ 800088