Abstract
Thrombocytopenia is common among sick neonates. Certain groups of thrombocytopenic adults respond favorably to the administration of recombinant thrombopoietin or to pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a recombinant human polypeptide that contains the 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 monkeys were divided into four groups and treated subcutaneously with 0.00, 0.25, 1.00, or 2.50 μg/kg once daily for 7 d. Complete blood counts, serum chemistries, clotting panels, and MGDF levels were followed serially, and hematopoietic progenitor cell assays were performed on bone marrow aspirates before the first dose and again on d 8. Pharmacokinetic evaluations were performed on the animals that received the highest dose of PEG-rHuMGDF. All monkeys had normal growth during the study period, and all chemistries, clotting studies, and blood pressure measurements were normal. The peak serum MGDF 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 rise on d 6, peaked on d 11, and returned to baseline by d 23. The two highest doses generated an 8- to 12-fold increase in platelets, whereas those treated with 0.25 μg/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) those that are effective in adult animals and did so without obvious short-term toxicity.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- rTpo:
-
recombinant thrombopoietin
- PEG-rHuMGDF:
-
pegylated recombinant human megakaryocyte growth and development factor
- NICU:
-
neonatal intensive care unit
- rEpo:
-
recombinant erythropoietin
- CFU-Mix:
-
pluripotent hematopoietic progenitor
- CFU-GM:
-
granulocyte-macrophage colony-forming unit
- BFU-E:
-
burst-forming unit-erythroid
- CFU-E:
-
colony-forming unit-erythroid
- AUC:
-
area under the serum concentration versus time curve
References
Kaushansky K 1995 Thrombopoietin: the primary regulator of platelet production. Blood 86: 419–431
de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ, Oles KJ, Hultgren B, Solberg LA Jr, Goeddel DV, Eaton DL 1994 Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369: 533–538
Lok S, Kaushansky K, Holly RD, Kuijper Jl, Lofton-Day CE, Oort PJ, Grant FJ, Heipel MD, Burkhead SK, Kramer JM, Bell LA, Sprecher CA, Blumberg H, Johnson R, Prunkard D, Hing AFT, Mathewes SL, Bailey MC, Forstrom JW, Buddle MM, Osborn SG, Evans SJ, Sheppard PO, Presnell SR, O'Hara PJ, Hagen FS, Roth GJ, Hagen Roth GJ, Foster DC 1994 Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369: 565–568
Zeigler FC, de Sauvage F, Widmer HR, Keller GA, Donahue C, Schreiber RD, Malloy B, Hass P, Eaton D, Matthews W 1994 In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. Blood 84: 4045–4052
Banu N, Wang JF, Deng B, Groopman JE, Avraham H 1995 Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. Blood 86: 1331–1338
Debili N, Wendling F, Katz A, Guichard J, Breton-Gorius J, Hunt P, Vainchenker W 1995 The Mpl ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. Blood 86: 2516–2525
Ulich TR, del Castillo J, Yin S, Swift S, Padilla D, Senaldi G, Bennett L, Shutter J, Bogenberger J, Sun D, Samal B, Shimamoto G, Lee R, Steinbrink R, Boone T, Sheridan WT, Hunt P 1995 Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood 86: 971–976
Harker LA, Hunt P, Marzec UM, Kelly AB, Tomer A, Hanson SR, Stead RB 1996 Regulation of platelet production and function by megakaryocyte growth and development factor in nonhuman primates. Blood 87: 1833–1844
Grossmann A, Lenox J, Ren HP, Humes JM, Forstrom JW, Kaushansky K, Sprugel KH 1996 Thrombopoietin accelerates platelet, red blood cell, and neutrophil recovery in myelosuppressed mice. Exp Hematol 24: 1238–1246
Basser RL, Rasko JEJ, Clarke K, Cebon J, Green MD, Hussein S, Alt C, Menchaca D, Tomita D, Marty J, Fox RM, Begley CG 1996 Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet 348: 1279–1281
Vadhan-Raj S, Murray LJ, Bueso-Ramos C, Patel S, Reddy SP, Hoots WK, Johnston T, Papadopolous NE, Hittelman WN, Johnston DA, Yang TA, Paton VE, Cohen RL, Hellmann SD, Benjamin RS, Broxmeyer HE 1997 Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 126: 673–681
Fanucchi M, Glaspy J, Crawford J, Garst J, Figlin R, Sheridan W, Menchaca D, Tomita D, Ozer H, Harker L 1997 Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med 336: 404–409
Basser RL, Rasko JEJ, Clarke K, Cebon J, Green MD, Grigg AP, Zalcberg J, Cohen B, O'Byrne J, Menchaca DM, Fox RM, Begley CG 1997 Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood 89: 3118–3128
Mehta P, Vasa R, Neumann L, Karpatkin M 1980 Thrombocytopenia in the high-risk infant. J Pediatr 97: 791–794
Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C 1986 Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 108: 749–755
Murray NA, Roberts IAG 1996 Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res 40: 112–119
Murray NA, Watts TL, Roberts IAG 1998 Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 43: 148–151
Andrew M, Castle V, Saigal S, Carter C, Kelton JG 1987 Clinical impact of neonatal thrombocytopenia. J Pediatr 110: 457–464
Nishihira H, Toyoda Y, Miyazaki H, Kigasawa H, Ohsaki E 1996 Growth of macroscopic human megakaryocyte colonies from cord blood in culture with recombinant human thrombopoietin (c-mpl ligand) and the effects of gestational age on frequency of colonies. Br J Haematol 92: 23–28
Sola MC, Christensen RD 1997 Use of hematopoietic growth factors in the neonatal intensive care unit. J Intensive Care Med 12: 187–205
George JW, Bracco CA, Shannon KM, Davis J, Smith IL, Phibbs RH, Hendrickx AG 1990 Age-related differences in erythropoietic response to recombinant human erythropoietin: comparison in adult and infant rhesus monkeys. Pediatr Res 28: 567–571
Kaushansky K 1998 Thrombopoietin. N Engl J Med 339: 746–754
Tarantal AF, Hendrickx AG 1988 The use of ultrasound for early pregnancy detection in the rhesus and cynomolgus macaque. J Med Primatol 17: 105–112
Tarantal AF, Hendrickx AG 1989 Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis). Teratology 39: 137–147
Tarantal AF, Gargosky SE, O'Brian WD, Hendrickx AG 1995 Hematologic and growth-related effects of frequent prenatal ultrasound exposure in the long-tailed macaque (Macaca fascicularis). Ultrasound Med Biol 21: 1073–1081
Andrew M, Kelton J 1984 Neonatal thrombocytopenia. Clinic Perinatol 11: 359–391
Sola MC, Juul SE, Meng YG, Garg S, Sims P, Calhoun DA, Dame JB, Christensen RD 1999 Thrombopoietin (Tpo) in the fetus and neonate: Tpo concentrations in preterm and term neonates, and organ distribution of Tpo and its receptor (c-mpl) during human fetal development. Early Hum Dev 53: 239–250
Sola MC, Calhoun DA, Hutson AD, Christensen RD 1999 Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit. Br J Haematol 104: 90–92
Farese AM, Hunt P, Boone T, MacVittie T 1996 Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates. Blood 86: 54–59
Harker LA, Marzec UM, Hunt P, Kelly AB, Tomer A, Cheung E, Hanson SR, Stead RB 1996 Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood 88: 511–521
Broudy VC, Lin NL, Sabath DF, Papayannopoulou T, Kaushansky 1997 Human platelets display high-affinity receptors for thrombopoietin. Blood 89: 1896–1904
Stefanich E, Senn T, Widmer R, Fratino C, Keller GA, Fielder PJ 1997 Metabolism of thrombopoietin (TPO) in vivo : determination of the binding dynamics for TPO in mice. Blood 89: 4063–4070
Fielder PJ, Hass P, Nagel M, Stefanich E, Widmer R, Bennett GL, Keller GA, de Sauvage FJ, Eaton D 1997 Human platelets as a model for the binding and degradation of thrombopoietin. Blood 89: 2782–2788
Rasko JEJ, Basser RL, Boyd J, Mansfield R, O'Malley CJ, Hussein S, Berndt MC, Clarke K, O'Byrne J, Sheridan WP, Grigg AP, Begley CG 1997 Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF. Br J Haematol 97: 871–880
Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, Davis AM, Tansik RL, Mattheakis LC, Boytos CM, Schatz PJ, Baccanari DP, Wrighton NC, Barrett RW, Dower WJ 1997 Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 276: 1696–1699
Boytos CM, Rudolph SK, Merrell C, DePrince R, Weigl D, de Serres M, Lalonde G 1998 Pegylated thrombopoietin-mimetic peptides elevate blood platelets and ablate the chemotherapy-induced platelet nadir in mice. Blood 92: 377A
Acknowledgements
The authors thank Lorin Roskos and Chris Reiber from Amgen, Inc. (Thousand Oaks, California) for running the PEG-rHuMGDF ELISA and for performing the pharmacokinetic analysis.
Author information
Authors and Affiliations
Additional information
Supported by an American Heart Association Fellowship Grant [M.C.S.], an award from the University of Florida Children's Miracle Network Telethon, and grants from the US Public Health Service: HL-44195, DK-49317, HL-55175, AI-32299, DK-53711.
Rights and permissions
About this article
Cite this article
Sola, M., Christensen, R., Hutson, A. et al. Pharmacokinetics, Pharmacodynamics, and Safety of Administering Pegylated Recombinant Megakaryocyte Growth and Development Factor to Newborn Rhesus Monkeys. Pediatr Res 47, 208 (2000). https://doi.org/10.1203/00006450-200002000-00010
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200002000-00010
This article is cited by
-
Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care?
Journal of Perinatology (2010)
-
Platelet reference ranges for neonates, defined using data from over 47 000 patients in a multihospital healthcare system
Journal of Perinatology (2009)
-
Strategien zur Behandlung von Thrombozytopenien im Kindesalter
Monatsschrift Kinderheilkunde (2006)
-
Epidemiologic and Outcome Studies of Patients Who Received Platelet Transfusions in the Neonatal Intensive Care Unit
Journal of Perinatology (2001)
