DDMODEL00000269: Morphine PK in paediatric population using bodyweight-dependent exponent (BDE) model

  public model
Short description:
Two executable files are available from the same publication, describing the PK of morphine in a wide paediatric age-range up to adults, using the bodyweight-based exponent (BDE) model for the developmental changes in clearance. The code for model I describes the PK of morphine alone, the code for model II describes the PK for both morphine and the morphine-3-glucuronide (M3G) metabolite.
Original code
  • Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model.
  • Wang C, Sadhavisvam S, Krekels EH, Dahan A, Tibboel D, Danhof M, Vinks AA, Knibbe CA
  • Clinical drug investigation, 7/2013, Volume 33, Issue 7, pages: 523-534
  • LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
  • Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range.Morphine and morphine-3-glucuronide (M3G) concentration data from 358 (pre)term neonates, infants, children and adults, and morphine concentration data from 117 adolescents were analysed using NONMEM 7.2. Based on available data, two models were developed: I. using morphine data; II. using morphine and M3G data.In model I, morphine clearance across the paediatric age range was very well described by a BDE function in which the allometric exponent decreased in a sigmoidal manner with bodyweight (BDE model) from 1.47 to 0.88, with half the decrease in exponent reached at 4.01 kg. In model II, the exponent for the formation and elimination clearance of M3G was found to decrease from 1.56 to 0.89 and from 1.06 to 0.61, with half the decrease reached at 3.89 and 4.87 kg, respectively. Using the BDE model, there was no need to use additional measures for size or age.The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age ranges between (pre)term neonates and adults by allowing the allometric exponent to decrease across the paediatric age range from values higher than 1 for neonates to values lower than 1 for infants and children.
Elke Krekels
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers);
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Morphine PK in paediatric population using bodyweight-dependent exponent (BDE) model;
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: Elke Krekels
  • Submitted: Dec 14, 2017 2:18:40 PM
  • Last Modified: Dec 14, 2017 2:18:40 PM
  • Version: 10 public model Download this version
    • Submitted on: Dec 14, 2017 2:18:40 PM
    • Submitted by: Elke Krekels
    • With comment: Edited model metadata online.