title: Development of Romiplostim for Treatment of Primary Immune Thrombocytopenia From a Pharmacokinetic and Pharmacodynamic Perspective.
abstract: Romiplostim is a novel thrombopoiesis-stimulating peptibody consisting of a carrier Fc domain and a peptide domain that binds to the thrombopoietin receptor (TPOR) on platelets and platelet precursors. Similar to endogenous thrombopoietin, romiplostim activates the TPOR to stimulate the growth and maturation of megakaryocytes, resulting in increased production of platelets in the circulation. Binding of romiplostim to TPOR on the platelets and megakaryocytes presumably triggers subsequent internalization and degradation. Therefore, increased platelet counts following romiplostim treatment results in increased elimination of the drug. The TPOR target-mediated process is saturable, resulting in nonlinear volume of distribution and clearance of romiplostim. Therefore, target-mediated disposition plays a decreasing role in drug elimination with increasing romiplostim serum concentration. Conversely, nonspecific elimination processes such as renal clearance play an increasing role with increasing romiplostim serum concentration. Limited pharmacokinetics data demonstrated that the exposure to romiplostim was lower after multiple dose administrations than after the first dose, although large inter-subject variability was observed. Large inter- and intra-subject variability in the platelet response was also observed at a given dose. These findings suggest considerable heterogeneity of disease in patients with primary immune thrombocytopenia and support the need for individual dose adjustments based on platelet counts.
authors.affiliation: Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA.
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Yang
authors.affiliation: Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.affiliation: Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Arkam
authors.affiliation: Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Franklin
authors.affiliation: Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA. chow@amgen.com.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chow
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy*; D051381:Rats; D011961:Receptors, Fc / Q000008:administration & dosage / Q000097:blood / Q000187:drug effects / Q000378:metabolism / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000187:drug effects* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000097:blood / Q000187:drug effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D034061:Thrombopoiesis / Q000187:drug effects; D013926:Thrombopoietin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim