Population pharmacokinetics of single-dose intravenous paracetamol in children

B. S. Mohammed, T. Engelhardt, G. A. Cameron, L. Cameron, G. M. Hawksworth, A. F. Hawwa, J. McElnay, P. J. Helms, J. S. McLay

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Abstract

To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children 15 yr of age.

After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3 at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM.

One hundred and fifty-nine blood samples from 33 children aged 1.815 yr, weight 13.756 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V-1 (central volume of distribution), Q (inter-compartmental clearance), and V-2 (peripheral volume of distribution) were: 16.51(WT/70)(0.75), 28.4(WT/70), 11.32(WT/70)(0.75), and 13.26(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V-1 and V-2 in litres).

In children aged 1.815 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V-1, V-2).

Original languageEnglish
Pages (from-to)823-829
Number of pages7
JournalBritish Journal of Anaesthesia
Volume108
Issue number5
Early online date1 Mar 2012
DOIs
Publication statusPublished - May 2012

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Keywords

  • children
  • intravenous
  • paracetamol
  • pharmacokinetics
  • acetaminophen pharmacokinetics
  • IV paracetemol
  • propacetamol
  • chlorzoxazone
  • clearance
  • tolerance
  • obesity
  • humans
  • CYP2E1
  • size

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