Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis1


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Abstract

SummaryBackgroundThe aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg·kg−1 (15 mg·kg−1 paracetamol) 6 h.MethodsA population pharmacokinetic analysis of paracetamol time–concentration profiles (846 observations) from 144 children [postconception age (PCA) 27 weeks–14 years] was undertaken using nonlinear mixed effects models (NONMEM). These data were taken from seven separate studies involving children given intravenous propacetamol. Time–concentration profiles (503 observations) from a further 86 children (PCA: 37 weeks–14 years) given paracetamol elixir orally were included in the analysis to assess relative bioavailability of intravenous propacetamol.ResultsA three-compartment (depot, central and peripheral) linear disposition model fitted data better than a two-compartment (depot and central) model. Population parameter estimates (between subject variability, %) were central volume (V2/Foral) 24 (55%) l · 70 kg−1, peripheral volume of distribution (V3/Foral) 30 (32%) l · 70 kg−1, clearance (CL/Foral) 16 (40%) l · h−1 · 70 kg−1 and intercompartment clearance (Q/Foral) 55 (116%) l · h−1 · 70 kg−1. Clearance increased from 27 weeks PCA (1.87 l·h−1 70 kg−1) to reach 84% of the mature value by 1 year of age (standardized to a 70 kg person using allometric ‘¼ power’ models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l·70 kg−1) to reach 110% of its mature value by 6 months of age. Central volume of distribution and intercompartment clearance did not change with age. Between occasions variability for the peripheral volume of distribution (V3/Foral) and clearance (CL/Foral) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (Ka 96 h−1) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5.ConclusionsA mean paracetamol serum concentration of 10 mg·l−1 is achieved in children 2–15 years given a standard dose of propacetamol 30 mg·kg−1 6 h. This concentration in the effect compartment is associated with a pain reduction of 2.6/10 after tonsillectomy and provides satisfactory analgesia for mild to moderate pain. Clearance is reduced in children less than 1 year of age and the target concentration of 10 mg·l−1 may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.

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