caa a22 4500 445313684 CHVBK 20180317142639.0 cr unu---uuuuu 170323e20110801xx s 000 0 eng 10.1007/s11095-011-0420-y doi (NATIONALLICENCE)springer-10.1007/s11095-011-0420-y Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism [Elektronische Daten] [Yow-Ming Wang, Bethlyn Sloey, Teresa Wong, Prerna Khandelwal, Rebeca Melara, Yu-Nien Sun] ABSTRACT: Purpose: Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG1. We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism. Methods: Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants. Results: FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination. Conclusion: Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent. Springer Science+Business Media, LLC, 2011 clearance mechanism nationallicence nonlinear pathway nationallicence pharmacokinetics nationallicence rodents nationallicence romiplostim nationallicence Wang Yow-Ming Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Sloey Bethlyn Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Wong Teresa Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Khandelwal Prerna Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Melara Rebeca Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Sun Yu-Nien Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/8(2011-08-01), 1931-1938 0724-8741 28:8<1931 2011 28 11095 https://doi.org/10.1007/s11095-011-0420-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0420-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang Yow-Ming Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Sloey Bethlyn Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Wong Teresa Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Khandelwal Prerna Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Melara Rebeca Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Sun Yu-Nien Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/8(2011-08-01), 1931-1938 0724-8741 28:8<1931 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer