title: Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration.
abstract: GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (<twofold) in cynomolgus monkeys following a 25 microg/kg s.c. dose and twofold following a 100 microg/kg s.c. dose. Because the plasma t1/2 of GW395058 is long in mouse, rat, dog, and monkey, yet the dose required to double platelet levels in monkeys is 50-fold that required in rats, differences in hematological responses may be due to interspecies differences in the interaction of GW395058 with the TPOr.
authors.affiliation: Department of International Development Support, Glaxo Wellcome Inc, Research Triangle Park, North Carolina 27709, USA.
authors.forename: M
authors.initials: M
authors.lastname: de Serres
authors.forename: R L
authors.initials: RL
authors.lastname: Yeager
authors.forename: J E
authors.initials: JE
authors.lastname: Dillberger
authors.forename: G
authors.initials: G
authors.lastname: Lalonde
authors.forename: G H
authors.initials: GH
authors.lastname: Gardner
authors.forename: C A
authors.initials: CA
authors.lastname: Rubens
authors.forename: A H
authors.initials: AH
authors.lastname: Simkins
authors.forename: J M
authors.initials: JM
authors.lastname: Sailstad
authors.forename: M J
authors.initials: MJ
authors.lastname: McNulty
authors.forename: J L
authors.initials: JL
authors.lastname: Woolley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000737:chemistry; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry; D013921:Thrombocytopenia / Q000188:drug therapy; D013926:Thrombopoietin / Q000737:chemistry
chemical_list: C400968:GW395058; D010455:Peptides; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin