DDMODEL00000271: Paracetamol and metabolite PK in newborns

  public model
Short description:
The model describes the PK of paracetamol and its sulphate and glucuronide metabolite in plasma and urine for term and preterm newborns.
Original code
  • Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants.
  • Krekels EH, van Ham S, de Hoon J, Tibboel D, Danhof M, Knibbe CA
  • European journal of clinical pharmacology, 9/2015, Volume 71, Issue 9, pages: 1075-1082
  • Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
  • Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach.A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses.Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation.Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.
Elke Krekels
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers);
Discrepancy between implemented model and original publication: The publication mentiones additive errors for the recovered amounts in urine, while these were in fact proportional. The uploaded code has the correct error model sturcture;
Model compliance with original publication: No;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The model describes the PK of paracetamol and its sulphate and glucuronide metabolite in plasma and urine for term and preterm newborns.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Metabolism;
Annotations are correct.
This model is not certified.
  • Model owner: Elke Krekels
  • Submitted: Dec 21, 2017 9:42:29 AM
  • Last Modified: Dec 21, 2017 9:42:29 AM
  • Version: 9 public model Download this version
    • Submitted on: Dec 21, 2017 9:42:29 AM
    • Submitted by: Elke Krekels
    • With comment: Edited model metadata online.