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The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large-Animal Model of Chemotherapy-Induced Thrombocytopenia

^a North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA;
^b Bioanalysis and Drug Metabolism, Clinical Pharmacology, Medicine Safety Evaluation Departments, Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA;

Key Words. Thrombocytopenia • Thrombopoietin • Mimetic peptide • GW395058 • Canine • Pharmacokinetics • Pharmacodynamics

Marlene L. Hauck, D.V.M., Ph.D., NCSU-CVM, 4700 Hillsborough St., Raleigh, North Carolina 27606, USA. Telephone: 919-513-6272; Fax: 919-513-6336; e-mail: marlene_hauck{at}ncsu.edu

GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimulates megakaryocytopoiesis and has previously been shown to increase platelet counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 were characterized using a randomized, crossover study in a large-animal model (dog) of chemotherapy-induced thrombocytopenia.

Nine beagle dogs received i.v. carboplatin (350 mg/m²) on day 0 and day 28. GW395058 (1.31 mg/kg) (n = 6) or vehicle control (n = 3) was administered on day 1 and day 29 either as an i.v. bolus or s.c. injection. After i.v. administration, peak concentrations of GW395058 occurred rapidly, while the half-life averaged approximately 56 h. Bioavailability (± standard deviation) of GW395058 given s.c. was 78.2% (20.9%).

GW395058 (i.v. and s.c.) ameliorated the platelet nadir (p = 0.0086) and resulted in a shorter time to recovery compared to the control group. The mean nadir platelet counts following carboplatin administration were 197,000 cells/µl (80,000) for the i.v. GW395058-dose group, 183,000 cells/µl (72,000) for the s.c.-dose group and 71,000 cells/µl (38,000) for the vehicle-alone group.

GW395058 reduced the thrombocytopenic effects of carboplatin in dogs. No GW395058-related adverse side effects were observed.

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