The pharmacokinetics and pharmacodynamics of GW395058, a peptide agonist of the thrombopoietin receptor, in the dog, a large-animal model of chemotherapy-induced thrombocytopenia

GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimu lates megakaryocytopoiesis and has previously been shown to increase platel et counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 we re characterized using a randomized, crossover study in a large-animal mode l (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 (rt = 3) was administered on day 1 and day 29 ei ther as an i.v. bolus or s.c. injection. lifter i.v. administration, peak c oncentrations of GW395058 occurred rapidly, while the half-life averaged ap proximately 56 h, Bioavailability (+/- standard deviation) of GW395058 give n 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 adm inistration were 197,000 cells/mu l (80,000) for the i.v. GW395058-dose group, 183,000 cells/mu l (72,000) for the s.c.-dose group an d 71,000 cells/mu l (38,000) for the vehicle-alone group, GW395058 reduced the thrombocytopenic effects of carboplatin in dogs, No GW 395058-related adverse side effects mere observed.