Paracetamol pharmacokinetics in term and preterm neonates.
Elke H.J. Krekels (1,2), Saskia van Ham (1), Karel Allegaert (3), Jan de Hoon (4), Dick Tibboel (2), Meindert Danhof (1), Catherijne A.J. Knibbe (1,2,5)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; (3) Neonatology, University Hospitals, Leuven, Belgium; (4) Center for Clinical Pharmacology, University Hospitals, Leuven, Belgium; (5) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
Objectives: Processes underlying drug disposition are continuously changing in the paediatric population, this is especially pronounced in neonates. Information on the influence of developmental changes on drug pharmacokinetics remains largely unidentified, but is essential for the development of rational dosing schemes. To describe the influence of the maturational changes on the pharmacokinetics of intravenous paracetamol in neonates, a population model was developed.
Methods: The analysis was based on a sparse dataset containing 457 paracetamol concentrations in blood and 154 paracetamol, 143 paracetamol glucuronide, and 154 paracetamol sulphate concentrations in urine from 70 preterm and term neonates who received intravenous propacetamol infusions [1-3]. The population pharmacokinetic model was developed using NONMEM VI and a systematic covariate analysis was performed to identify the best descriptor for the maturational changes in the pharmacokinetics of paracetamol.
Results: The time-course of paracetamol was best described with a one-compartment model in which changes in the distribution volume were best described with a linear bodyweight-based equation. Both renal excretion of unchanged paracetamol and paracetamol glucuronidation were found to scale linearly with bodyweight whereas paracetamol sulphation was found to increase exponentially with bodyweight with an exponent of 1.29. In the model, no up-regulation in paracetamol glucuronidation was found upon multiple dosing. Previous reports of increased glucuronidation ratios in urine may be explained by slower elimination through the glucuronidation route compared to the other two routes.
Conclusions: Many physiological changes take place within the first month of life and the influence of these changes on paracetamol PK have now been described. How the observed maturational changes extrapolate beyond the neonatal period is part of future investigations.
 Allegaert et al. Eur J Clin Pharmacol 60(3); 191-197 (2004)
 Allegaert et al. Arch Dis Child Fetal Neonatal Ed 89(1); F25-F28 (2004)
 Allegaert et al. Acta Paediatr 94(9); 1273-1279 (2005)