DDMODEL00000248: Morphine PK in children younger than three years

  public model
Short description:
The publication on the Original model can be found here: Clin Pharmacokinet. 2009;48(6):371-85. doi: 10.2165/00003088-200948060-00003 This code uses the same structural model, but with initials estimates that are updated to the final values of the fit of a dataset that combined both internal and external data as published here: Clin Pharmacokinet. 2011 Jan;50(1):51-63. doi: 10.2165/11536750-000000000-00000.
Original code
  • Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children.
  • Krekels EH, DeJongh J, van Lingen RA, van der Marel CD, Choonara I, Lynn AM, Danhof M, Tibboel D, Knibbe CA
  • Clinical pharmacokinetics, 1/2011, Volume 50, Issue 1, pages: 51-63
  • Division of Pharmacology, LeidenAmsterdam Center for Drug Research, Leiden, The Netherlands.
  • 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.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.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.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.
Catherijne Knibbe
Context of model development: Dose & Schedule Selection and Label Recommendation;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Population PK model for morphine in postoperative newborns (including preterm newborns), infants and toddlers younger than three years of age.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: CNS;
Annotations are correct.
This model is not certified.
  • Model owner: Catherijne Knibbe
  • Submitted: Oct 9, 2017 1:05:54 PM
  • Last Modified: Oct 9, 2017 1:05:54 PM
  • Version: 10 public model Download this version
    • Submitted on: Oct 9, 2017 1:05:54 PM
    • Submitted by: Catherijne Knibbe
    • With comment: Edited model metadata online.