title: A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain.
abstract: OBJECTIVE
  To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation.
  
  
  METHODS
  Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration.
  
  
  RESULTS
  The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses ≥ 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient.
  
  
  CONCLUSIONS
  This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. rasmusvjuul@gmail.com.
authors.forename: Rasmus Vestergaard
authors.initials: RV
authors.lastname: Juul
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Nyberg
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Trine Meldgaard
authors.initials: TM
authors.lastname: Lund
authors.affiliation: Orthopaedic Surgery Research Unit, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Sten
authors.initials: S
authors.lastname: Rasmussen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Lona Louring
authors.initials: LL
authors.lastname: Christrup
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D010149:Postoperative Pain / Q000188:drug therapy*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: non-linear mixed effects modeling; opioid consumption; pharmacokinetics-pharmacodynamics; postoperative pain; repeated time to event