DOSE-RESPONSE EFFECTS OF PEGYLATED HUMAN MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR ON PLATELET PRODUCTION AND FUNCTION IN NONHUMAN-PRIMATES

Thrombopoietin (TPO) is the physiologic Mpl-ligand regulating platelet production. Pegylated human recombinant megakaryocyte growth and deve lopment factor (PEG-rHuMGDF), a truncated polypeptide Mpl-ligand deriv itized with poly-(ethylene glycol), induces megakaryocyte endoreduplic ation and proliferation in vitro and in vivo. In the present study, th e dose-response effects of PEG-rHuMGDF on pharmacokinetics, megakaryoc ytopoiesis, platelet production, and platelet function were characteri zed for dosing 0.05, 0.10, 0.50, or 2.5 mu g/kg/d in 22 baboons for 28 days. Daily subcutaneous injections of PEG-rHuMGDF produced linear lo g-dose responses in (1) steady-state trough plasma levels of PEG-HuMGD F (P < 10(-3)); (2) marrow megakaryocyte volume (P < 10(-3)), ploidy ( P < 10(-4)), and number (P < .01); and (3) peripheral platelet concent rations (P < 10(-4)) and platelet mass turnover (P < 10(-3)). Platelet morphology, life span, and recovery were normal, and peripheral leuko cyte, neutrophil, and erythrocyte counts were not significantly affect ed by PEG-rHuMGDF (P > .1 in all cases). PEG-rHUMGDF at 0.5 mu g/kg/d produced similar blood concentrations of Mpl-ligand and platelets as 1 0 times the dose of rHuMGDF (5.0 mu g/kg/d), reflecting the extended p lasma half-life achieved through pegylation. Whereas PEG-rHuMGDF did n ot induce platelet aggregation in vitro, platelet aggregatory responsi veness induced by thrombin receptor agonist peptide (TRAP(1-6)) and co llagen was transiently enhanced ex vivo during the initial few days of PEG-rHuMGDF administration. However, adenosine diphosphate (ADP)-indu ced platelet aggregation was not enhanced ex vivo by PEG-rHuMGDF thera py. In-111-platelet deposition on segments of homologous endarterectom ized aorta (EA) and vascular graft (VG) interposed in arteriovenous fe moral shunts increased in direct proportion to the circulating platele t concentration (P < 10(-4) for both EA and VG); I-125-fibrin accumula tion was not affected by PEG-rHuMGDF-induced increases in peripheral p latelet counts. Changes in platelet production and function produced b y PEG-rHuMGDF returned to baseline within 2 weeks after discontinuing treatment. Thus, in nonhuman primates, PEG-rHuMGDF increases platelet production in a linear log-dose-dependent manner by stimulating megaka ryocyte endoreduplication and new megakaryocyte formation from marrow hematopoietic progenitors. These findings suggest that appropriate dos ing of PEG-rHuMGDF therapy during periods of chemotherapy-induced marr ow suppression may maintain hemostatic concentrations of peripheral pl atelets without increasing the risk of thrombosis. (C) 1996 by The Ame rican Society of Hematology.