Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals
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RESEARCH PAPER
Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals Wojciech Krzyzanski & Liviawati Sutjandra & Juan Jose Perez-Ruixo & Bethlyn Sloey & Andrew T. Chow & Yow-Ming Wang
Received: 21 June 2012 / Accepted: 24 September 2012 / Published online: 19 December 2012 # Springer Science+Business Media, LLC 2012
ABSTRACT Purpose Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamicmediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined. Methods The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, ROthr, and K D parameters were determinants of drug potency, whereas Smax reflected drug efficacy. Results The model implicated that receptor-mediated clearance was negligible. RO thr estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of KD were 4.05, 2320, and 429 ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship. Conclusions The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys,
and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.
W. Krzyzanski Department of Pharmaceutical Sciences, University at Buffalo Buffalo, New York, USA
Y.-M. Wang Office of Clinical Pharmacology, Food and Drug Administration Washington, District of Columbia, USA
L. Sutjandra : J. J. Perez-Ruixo : B. Sloey : A. T. Chow Amgen Inc., Pharmacokinetics and Drug Metabolism Thousand Oaks, California, USA
J. J. Perez-Ruixo (*) Quantitative Pharmacology Pharmacokinetics and Drug Metabolism Department, Amgen Inc. Picayo 3, Puzol 46530 Valencia, Spain e-mail: [email protected]
KEY WORDS c-Mpl receptor . peptibody . pharmacodynamics-mediated drug disposition (PDMDD) . pharmacokinetic and pharmacodynamic modeling ABBREVIATIONS AUC0-∞ area under the curve from 0 to infinity BaF3-Mpl cells Mpl-transfected cells CFU colony-forming unit CL clearance CV coefficient of variation DIV intravenous dosing ELISA enzyme-linked immunosorbent assay eTPO endogenous TPO IgG1 human immunoglobulin G subtype 1 ITS iterative-two-stage rHu-TPO recombinant human thrombopoietin TPO thrombopoietin
INTRODUCTION Megakaryocytopoiesis is a continuous developmental process of platelet production regulated by a complex
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network of hematopoietic growth factors. In this process, hematopoiet
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