title: Investigation of the pharmacokinetics of romiplostim in rodents with a focus on the clearance mechanism.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.
authors.affiliation: Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, Thousand Oaks, California 91320, USA. wang.yowming@gmail.com
authors.forename: Yow-Ming C
authors.initials: YM
authors.lastname: Wang
authors.forename: Bethlyn
authors.initials: B
authors.lastname: Sloey
authors.forename: Teresa
authors.initials: T
authors.lastname: Wong
authors.forename: Prerna
authors.initials: P
authors.lastname: Khandelwal
authors.forename: Rebeca
authors.initials: R
authors.lastname: Melara
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000008:administration & dosage / Q000097:blood; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013156:Splenectomy; D013926:Thrombopoietin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013926:Thrombopoietin; C488777:romiplostim