Hematopoietic recovery following autologous bone marrow transplantation in a nonhuman primate: effect of variation in treatment schedule with PEG-rHuMGDF.
Mathematical modeling of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) pharmacokinetics (PK) and pharmacodynamics (PD) suggest that variations in the PEG-rHuMGDF treatment schedule could reduce the severity and duration of thrombocytopenia following myeloablation and bone marrow transplant (BMT). We tested this hypothesis in a rhesus monkey model of autologous (Au) bone marrow-derived mononuclear cell (BM-MNC) transplantation following lethal myeloablation. On day 0, animals were myeloablated by total body exposure to 920 cGy, 250 kVp x-irradiation (TBI). Four cohorts of animals were infused with 1 x 10(8) AuBM-MNC/kg body weight within 2 hours of TBI. The AuBMT-alone cohort received no cytokine, the daily dosage cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) post TBI and AuBMT, and the pre/post-transplant cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) pre (day -9 to day -5) and post TBI and AuBMT. The post-transplant PEG-rHuMGDF administration in the above cohorts was begun on day 1 post TBI and continued until platelet counts reached 200,000 micro l (range, 15-31 days). Another group received PEG-rHuMGDF (300 micro g/kg/day, s.c.) on days 1 and 3 only following TBI and AuBMT. The TBI controls received neither AuBMT nor cytokine therapy. In this model of AuBMT, with regard to the PEG-rHuMGDF administration schedule, the daily dosage of the post-transplant cohort did not significantly improve platelet recovery; the pre/post-transplant schedule and an abbreviated high-dosage, post-transplant schedule (days 1 and 3) significantly improved the duration and nadir of thrombocytopenia and platelet recovery. These data confirm predictions from PK/PD modeling of PEG-rHuMGDF that thrombocytopenia is preventable following AuBMT.
Farese
Ann M
AM
University of Maryland Greenebaum Cancer Center, Baltimore, Maryland 21201, USA. afarese@umaryland.edu
MacVittie
Thomas J
TJ
Roskos
Lorin
L
Stead
Richard B
RB
D000818:Animals; D001855:Bone Marrow Diseases / Q000209:etiology / Q000628:therapy; D016026:Bone Marrow Transplantation / Q000379:methods*; D003114:Colony-Forming Units Assay / Q000379:methods; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012107:Research Design; D013926:Thrombopoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation / Q000009:adverse effects / Q000379:methods
D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin