Pharmacokinetics, pharmacodynamics, and safety of administering pegylated recombinant megakaryocyte growth and development factor to newborn rhesus monkeys

Thrombocytopenia is common among sick neonates. Certain groups of thrombocy topenic adults respond favorably to the administration of recombinant throm bopoietin or to pegylated recombinant human megakaryocyte growth and develo pment factor (PEG-rHuMGDF), a recombinant human polypeptide that contains t he receptor-binding N-terminal domain of thrombopoietin. The effectiveness and safety of such treatment in neonates, however, have not been reported. The purpose of the present study was to determine the biologic activity and safety of PEG-rHuMGDF administration to newborn rhesus monkeys. Eight monk eys were divided into four groups and treated subcutaneously with 0.00, 0.2 5, 1.00, or 2.50 mu g/kg once daily for 7 d. Complete blood counts, serum c hemistries, clotting panels, and MGDF levels were followed serially, and he matopoietic progenitor cell assays were performed on bone marrow aspirates before the first dose and again on d 8. Pharmacokinetic evaluations were pe rformed on the animals that received the highest dose of PEG-rHuMGDF. All m onkeys had normal growth during the study period, and all chemistries, clot ting studies, and blood pressure measurements were normal. The peak serum M GDF concentration occurred at 3 h, and the half-life was 8.4 to 13.0 h. As in adult rhesus monkeys, platelet counts in the treated neonates began to r ise on d 6, peaked on d II, and returned to baseline by d 23. The two highe st doses generated an 8- to 12-fold increase in platelets, whereas those tr eated with 0.25 mu g/kg had a 6-fold increase. Other hematologic parameters measured were unaffected. Thus, newborn monkeys responded to doses of PEG- rHuMGDF that were similar to or smaller than (per kilogram body weight) tho se that are effective in adult animals and did so without obvious short-ter m toxicity.