title: Simplification of a pharmacokinetic model for red blood cell methotrexate disposition.
abstract: OBJECTIVE
  A pharmacokinetic (PK) model is available for describing the time course of the concentrations of methotrexate (MTX or MTXGlu1) and its active polyglutamated metabolites (MTXGlu2-5) in red blood cells (RBCs). In this study, we aimed to simplify the MTX PK model and to optimise the blood sampling schedules for use in future studies.
  
  
  METHODS
  A proper lumping technique was used to simplify the original MTX RBC PK model. The sum of predicted RBC MTXGlu3-5 concentrations in both the simplified and original models was compared. The sampling schedules for MTXGlu3-5 or all MTX polyglutamates in RBCs were optimised using the Population OPTimal design (POPT) software.
  
  
  RESULTS
  The MTX RBC PK model was simplified into a three-state model. The maximum of the absolute value of relative difference in the sum of predicted RBC MTXGlu3-5 concentrations over time was 6.3 %. A five blood sample design was identified for estimating parameters of the simplified model.
  
  
  CONCLUSIONS
  This study illustrates the application of model simplification processes to an existing model for MTX RBC PK. The same techniques illustrated in our study may be adopted by other studies with similar interest.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand. shan.pan@otago.ac.nz.
authors.forename: Shan
authors.initials: S
authors.lastname: Pan
authors.affiliation: Model Answers Pty Ltd, Brisbane, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Korell
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
mesh_terms: D018501:Antirheumatic Agents / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008954:Models, Biological; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012984:Software
chemical_list: D018501:Antirheumatic Agents; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate
keywords: Lumping; Methotrexate; Optimal design; Pharmacokinetic; Structural identifiability