Get access

Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults

Authors

  • Chenguang Wang,

    1. Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
    2. Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Intensive Care, Rotterdam, The Netherlands
    Search for more papers by this author
  • Karel Allegaert,

    1. Department of Development and Regeneration, KU Leuven and Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
    Search for more papers by this author
  • Dick Tibboel,

    1. Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Intensive Care, Rotterdam, The Netherlands
    Search for more papers by this author
  • Meindert Danhof,

    1. Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
    Search for more papers by this author
  • Caroline D. van der Marel,

    1. Department of Anesthesiology, Erasmus MC, Rotterdam, The Netherlands
    Search for more papers by this author
  • Ron A.A. Mathot,

    1. Departments of Hospital Pharmacy and Clinical Pharmacology, Academic Medical Centre, Amsterdam, The Netherlands
    Search for more papers by this author
  • Catherijne A.J. Knibbe

    Corresponding author
    1. Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
    2. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
    • Corresponding Author:

      Prof. Dr. Catherijne A.J. Knibbe, St. Antonius Hospital, Department of Clinical Pharmacy, P.O. Box 2500, 3430 EM Nieuwegein

      Email: c.knibbe@antoniusziekenhuis.nl

    Search for more papers by this author

Abstract

In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific focus on clearance. Concentration-time data obtained in 220 neonates (post-natal age 1–76 days, gestational age 27–42 weeks), infants (0.11–1.33 yrs), children (2–7 yrs) and adults (19–34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent were tested. Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight-dependent exponent k was identified (CLi = CLp × (BW/70)k). The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2 kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age-range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges.

Ancillary