Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis 1

• Published in: Pediatric anesthesia Vol. 15; no. 4; pp. 282 - 292
• Main Authors: ANDERSON, BRIAN J., PONS, GERARD, AUTRET‐LECA, ELISABETH, ALLEGAERT, KAREL, BOCCARD, ERIC
• Format: Journal Article
• Language: English
• Published: 01.04.2005
• ISSN: 1155-5645; 1460-9592
• DOI: 10.1111/j.1460-9592.2005.01455.x

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. Methods:  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 ‘ 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.