title: The pharmacokinetics and pharmacodynamics of GW395058, a peptide agonist of the thrombopoietin receptor, in the dog, a large-animal model of chemotherapy-induced thrombocytopenia.
abstract: 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/m(2)) 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/microl (80,000) for the i.v. GW395058-dose group, 183,000 cells/microl (72,000) for the s.c.-dose group and 71,000 cells/microl (38,000) for the vehicle-alone group. GW395058 reduced the thrombocytopenic effects of carboplatin in dogs. No GW395058-related adverse side effects were observed.
authors.affiliation: North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Case
authors.forename: M L
authors.initials: ML
authors.lastname: Hauck
authors.forename: R L
authors.initials: RL
authors.lastname: Yeager
authors.forename: A H
authors.initials: AH
authors.lastname: Simkins
authors.forename: M
authors.initials: M
authors.lastname: de Serres
authors.forename: V D
authors.initials: VD
authors.lastname: Schmith
authors.forename: J E
authors.initials: JE
authors.lastname: Dillberger
authors.forename: R L
authors.initials: RL
authors.lastname: Page
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000633:toxicity*; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate; D018716:Molecular Mimicry; D009363:Neoplasm Proteins; D009504:Neutrophils / Q000187:drug effects; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000502:physiology*; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000628:therapy*; D013926:Thrombopoietin / Q000502:physiology
chemical_list: C400968:GW395058; D009363:Neoplasm Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; D016190:Carboplatin