| Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism. | |
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MedLine Citation:
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PMID: 21476045 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 IgG(1). 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. |
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Authors:
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Yow-Ming C Wang; Bethlyn Sloey; Teresa Wong; Prerna Khandelwal; Rebeca Melara; Yu-Nien Sun |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-8 |
Journal Detail:
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Title: Pharmaceutical research Volume: - ISSN: 1573-904X ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, Thousand Oaks, California, 91320, USA, wang.yowming@gmail.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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