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 x kg(-1) (15 mg x 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 (V2/F(oral)) 24 (55%) l x 70 kg(-1), peripheral volume of distribution (V3/F(oral)) 30 (32%) l x 70 kg(-1), clearance (CL/F(oral)) 16 (40%) l x h(-1) x 70 kg(-1) and intercompartment clearance (Q/F(oral)) 55 (116%) l x h(-1) x 70 kg(-1). Clearance increased from 27 weeks PCA (1.87 l x 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 x 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/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 x l(-1) is achieved in children 2-15 years given a standard dose of propacetamol 30 mg x 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 x l(-1) may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.
Anderson
Brian J
BJ
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. briana@adhb.govt.nz
Pons
Gerard
G
Autret-Leca
Elisabeth
E
Allegaert
Karel
K
Boccard
Eric
E
D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000293:Adolescent; D000465:Algorithms; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D017321:Clinical Trials, Phase I as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D017711:Nonlinear Dynamics; D010149:Postoperative Pain / Q000188:drug therapy; D011153:Population; D014068:Tonsillectomy
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen