Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis

Background: The 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. Methhods: A 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. Results: A 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 (V-2/F-oral) 24 (55%) l . 70 kg(-1), peripheral volume of distribution (V-3/F-oral) 30 (32%) l . 70 kg(-1), clearance (CL/F-oral) 16 (40%) l . h(-1) . 70 kg(-1) and intercompartment clearance (Q/F-oral) 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 '1/4 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 (V-3/F-oral) and clearance (CL/F-oral) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (K-a 96 h(-1)) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5. Conclusions: A 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.