Purpose: 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. Methods: 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. Results: Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg<sup>1.4</sup>, 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. Conclusions: Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.

Additional Metadata
Keywords Glucuronidation, Multiple dosing, Paediatrics, Paracetamol
Persistent URL dx.doi.org/10.1007/s00228-015-1887-y, hdl.handle.net/1765/92210
Journal European Journal of Clinical Pharmacology
Krekels, E.H.J, Van Ham, S, Allegaert, K.M, de Hoon, J.N, Tibboel, D, Danhof, M, & Knibbe, C.A.J. (2015). Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants. European Journal of Clinical Pharmacology, 71(9), 1075–1082. doi:10.1007/s00228-015-1887-y