Open AccessThe Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large‐Animal Model of Chemotherapy‐Induced Thrombocytopenia
Author(s) -
Case Beth C.,
Hauck Marlene L.,
Yeager Russell L.,
Simkins Anita H.,
de Serres Mark,
Schmith Virginia D.,
Dillberger John E.,
Page Rodney L.
Publication year - 2000
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.18-5-360
Subject(s) - thrombopoietin receptor , thrombopoietin , megakaryocytopoiesis , pharmacokinetics , pharmacology , agonist , biology , pharmacodynamics , platelet , in vivo , receptor , megakaryocyte , crossover study , chemotherapy , medicine , immunology , haematopoiesis , stem cell , pathology , biochemistry , microbiology and biotechnology , genetics , alternative medicine , placebo
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/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.