title: Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children.
abstract: OBJECTIVE
  Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model.
  
  
  METHODS
  Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model.
  
  
  RESULTS
  The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH.
  
  
  CONCLUSIONS
  The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.|LAP&P Consultants BV, Leiden, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: DeJongh
authors.affiliation: Princess Amalia Department of Pediatrics, Division of Neonatology, Isala Clinics, Zwolle, The Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: van Lingen
authors.affiliation: Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Caroline D
authors.initials: CD
authors.lastname: van der Marel
authors.affiliation: Academic Division of Child Health, University of Nottingham, Derbyshire Children's Hospital, Derby, UK.
authors.forename: Imti
authors.initials: I
authors.lastname: Choonara
authors.affiliation: Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital/University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lynn
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands. c.knibbe@antoniusziekenhuis.nl.|Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. c.knibbe@antoniusziekenhuis.nl.|Department of Clinical Pharmacy, St Antonius Hospital, PO Box 2500, 3430 EM, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl.
authors.forename: Catherijne
authors.initials: C
authors.lastname: Knibbe