title: Pharmacokinetic and pharmacodynamic modeling of romiplostim in animals.
abstract: OBJECTIVE
  Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated 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, RO(thr), and K(D) parameters were determinants of drug potency, whereas S(max) 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 K(D) 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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
authors.forename: Liviawati
authors.initials: L
authors.lastname: Sutjandra
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez-Ruixo
authors.forename: Bethlyn
authors.initials: B
authors.lastname: Sloey
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chow
authors.forename: Yow-Ming
authors.initials: YM
authors.lastname: Wang
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008954:Models, Biological; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000097:blood; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D034061:Thrombopoiesis / Q000187:drug effects; D013926:Thrombopoietin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim