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Pharmacokinetics and Hematological Effects of the PEGylated Thrombopoietin Peptide Mimetic GW395058 in Rats and Monkeys After Intravenous or Subcutaneous Administration

^a Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA;
^b Affymax Research Institute, Palo Alto, California, USA

Key Words. Thrombopoietin • Mimetic peptide • GW395058 • Pharmacokinetics • Hematology • Rat • Monkey • PEGylated

Dr. Mark de Serres, Division of Bioanalysis and Drug Metabolism, Department of International Development Support, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.

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 µg/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 µg/kg) serum t (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t 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 µg/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 µg/kg s.c. dose and twofold following a 100 µg/kg s.c. dose. Because the plasma t 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.

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