TY - JOUR
T1 - Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates
AU - Harker, Laurence A.
AU - Marzec, Ulla M.
AU - Hunt, Pamela
AU - Kelly, Andrew B.
AU - Tomer, Aaron
AU - Cheung, Ellen
AU - Hanson, Stephen R.
AU - Stead, Richard B.
PY - 1996/7/15
Y1 - 1996/7/15
N2 - Thrombopoietin (TPO) is the physiologic Mpl-ligand regulating platelet production. Pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated polypeptide Mpl-ligand derivitized with poly-(ethylene glycol), induces megakaryocyte endoreduplication and proliferation in vitro and in vivo. In the present study, the dose-response effects of PEG-rHuMGDF on pharmacokinetics, megakaryocytopoiesis, platelet production, and platelet function were characterized for dosing 0.05, 0.10, 0.50, or 2.5 μg/kg/d in 22 baboons for 28 days. Daily subcutaneous injections of PEG-rHuMGDF produced linear log-dose responses in (1) steady- state trough plasma levels of PEG-HuMGDF (P < 10-3); (2) marrow megakaryocyte volume (P < 10-3), ploidy (P < 10-4), and number (P < .01); and (3) peripheral platelet concentrations (P < 10-4) and platelet mass turnover (P < 10-3). Platelet morphology, life span, and recovery were normal, and peripheral leukocyte, neutrophil, and erythrocyte counts were not significantly affected by PEG-rHuMGDF (P > .1 in all cases), PEG-rHuMGDF at 0.5 μg/kg/d produced similar blood concentrations of Mpl-ligand and platelets as 10 times the dose of rHuMGDF (5.0 μg/kg/d), reflecting the extended plasma half-life achieved through pegylation. Whereas PEG-rHuMGDF did not induce platelet aggregation in vitro, platelet aggregatory responsiveness induced by thrombin receptor agonist peptide (TRAP1-5) and collagen was transiently enhanced ex vivo during the initial few days of PEG- rHuMGDF administration. However, adenosine diphosphate (ADP)-induced platelet aggregation was not enhanced ex vivo by PEG-rHuMGDF therapy. 111In- platelet deposition on segments of homologous endarterectomized aorta (EA) and vascular graft (VG) interposed in arteriovenous femoral shunts increased in direct proportion to the circulating platelet concentration (P < 10-4 for both EA and VG); 125I-fibrin accumulation was not affected by PEG- rHuMGDF-induced increases in peripheral platelet counts. Changes in platelet production and function produced by 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 megakaryocyte endoreduplication and new megakaryocyte formation from marrow hematopoietic progenitors. These findings suggest that appropriate dosing of PEG-rHuMGDF therapy during periods of chemotherapy- induced marrow suppression may maintain hemostatic concentrations of peripheral platelets without increasing the risk of thrombosis.
AB - Thrombopoietin (TPO) is the physiologic Mpl-ligand regulating platelet production. Pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated polypeptide Mpl-ligand derivitized with poly-(ethylene glycol), induces megakaryocyte endoreduplication and proliferation in vitro and in vivo. In the present study, the dose-response effects of PEG-rHuMGDF on pharmacokinetics, megakaryocytopoiesis, platelet production, and platelet function were characterized for dosing 0.05, 0.10, 0.50, or 2.5 μg/kg/d in 22 baboons for 28 days. Daily subcutaneous injections of PEG-rHuMGDF produced linear log-dose responses in (1) steady- state trough plasma levels of PEG-HuMGDF (P < 10-3); (2) marrow megakaryocyte volume (P < 10-3), ploidy (P < 10-4), and number (P < .01); and (3) peripheral platelet concentrations (P < 10-4) and platelet mass turnover (P < 10-3). Platelet morphology, life span, and recovery were normal, and peripheral leukocyte, neutrophil, and erythrocyte counts were not significantly affected by PEG-rHuMGDF (P > .1 in all cases), PEG-rHuMGDF at 0.5 μg/kg/d produced similar blood concentrations of Mpl-ligand and platelets as 10 times the dose of rHuMGDF (5.0 μg/kg/d), reflecting the extended plasma half-life achieved through pegylation. Whereas PEG-rHuMGDF did not induce platelet aggregation in vitro, platelet aggregatory responsiveness induced by thrombin receptor agonist peptide (TRAP1-5) and collagen was transiently enhanced ex vivo during the initial few days of PEG- rHuMGDF administration. However, adenosine diphosphate (ADP)-induced platelet aggregation was not enhanced ex vivo by PEG-rHuMGDF therapy. 111In- platelet deposition on segments of homologous endarterectomized aorta (EA) and vascular graft (VG) interposed in arteriovenous femoral shunts increased in direct proportion to the circulating platelet concentration (P < 10-4 for both EA and VG); 125I-fibrin accumulation was not affected by PEG- rHuMGDF-induced increases in peripheral platelet counts. Changes in platelet production and function produced by 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 megakaryocyte endoreduplication and new megakaryocyte formation from marrow hematopoietic progenitors. These findings suggest that appropriate dosing of PEG-rHuMGDF therapy during periods of chemotherapy- induced marrow suppression may maintain hemostatic concentrations of peripheral platelets without increasing the risk of thrombosis.
UR - http://www.scopus.com/inward/record.url?scp=0029943307&partnerID=8YFLogxK
U2 - 10.1182/blood.v88.2.511.bloodjournal882511
DO - 10.1182/blood.v88.2.511.bloodjournal882511
M3 - Article
AN - SCOPUS:0029943307
SN - 0006-4971
VL - 88
SP - 511
EP - 521
JO - Blood
JF - Blood
IS - 2
ER -