Abstract 1558
Neonatal Immunology & Hematology Poster Symposium, Monday, 5/3
Thrombocytopenia is common among sick neonates. Certain groups of thrombocytopenic adults respond favorably to the administration of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a polypeptide that contains the receptor-binding N-terminal domain of thrombopoietin. The effectiveness and safety of such treatment in neonates are not known. This study was designed to determine the biological activity and safety of PEG-rHuMGDF administration to newborn rhesus monkeys. Eight newborn monkeys were divided in four groups, and treated with 0.00, 0.25, 1.00, or 2.50 ug/kg once-daily for seven days, starting on the first day of life. Blood counts, serum chemistries, clotting panels, and MGDF levels were followed serially, and hematopoietic progenitor cell assays were performed on bone marrow and blood samples before the first and after the last dose. Pharmacokinetic evaluations were performed on those receiving the highest dose. All monkeys had normal growth during the study period, and all chemistries, clotting studies, and blood pressure measurements were normal. The peak MGDF was at 3 hrs and the half-life was 8.4 to 13.0 hrs. As in adult monkeys, platelet counts began to rise on day 6, peaked on day 11, and returned to baseline by day 23. The two highest doses generated an 8- to 12- fold increase in platelets; the 0.25 ug/kg dose generated a 6-fold increase. Treatment had no effect on CFU-Mix, CFU-GM, BFU-E or CFU-E, but induced an increase in megakaryocytes progenitors in the marrow (131±188%) and blood (189±327%). Thus, newborn monkeys responded to a smaller dose of PEG-rHuMGDF (per kg body wt) than adult monkeys, with no obvious short term toxicity. On the basis of these studies, we predict that PEG-rHuMGDF will have a thrombopoietic effect on thrombocytopenic human neonates and that lower doses/kg will be required in neonates than in adults.
