title: Effective use of modeling and simulation in designing bioequivalence and comparability studies of large-molecule compounds: the case of erythropoietin.
abstract: OBJECTIVE
  Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug.
  
  
  METHODS
  A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples.
  
  
  RESULTS
  The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy-time curve, and most for the maximum serum concentration of erythropoietin.
  
  
  CONCLUSIONS
  These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Nakai
authors.forename: Kumiko
authors.initials: K
authors.lastname: Miyata
authors.forename: Satofumi
authors.initials: S
authors.lastname: Iida
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kawanishi
mesh_terms: D019540:Area Under Curve; D003198:Computer Simulation; D018592:Cross-Over Studies; D016903:Drug Monitoring; D004921:Erythropoietin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006397:Hematinics / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D008970:Molecular Weight; D012107:Research Design; D017701:Reticulocyte Count; D012984:Software; D013810:Therapeutic Equivalency
chemical_list: D006397:Hematinics; D004921:Erythropoietin