Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates.
BACKGROUND
The aim of this study was to describe propacetamol pharmacokinetics in term and preterm neonates to suggest dosing regimens. METHODS. A population pharmacokinetic analysis of paracetamol (acetaminophen) time-concentration profiles in 48 neonates was undertaken using non-linear mixed-effects models. Neonates were given either single (n=30) or multiple doses (n=18) of propacetamol infusion over 15 min. Neonates had a median postnatal age of 1 day (range, 1-76 days). Median post-conceptual age (PCA) was 35 weeks (range, 27-42 weeks), and median weight was 2.4 kg (range, 0.51-4 kg).


RESULTS
The population volume of distribution estimate and between-subject variability (%) for a one-compartment model with zero-order input and first-order elimination was 70.4 l (30.7%)/70 kg. Clearance increased from 2.85 l/70 kg, CV 40.7% at 27 weeks PCA to reach 7.05 l/h per 70 kg by 42 weeks PCA (standardised to a 70-kg person using allometric "1/4-power" models). Between-occasion variability for volume of distribution and clearance were 17.4% and 26%, respectively.


CONCLUSIONS
A mean paracetamol steady-state target concentration above 10 mg/l at trough can be achieved using a loading dose of 40 mg/kg and maintenance doses of 20 mg/kg 6 h in 28-week PCA neonates, 25 mg/kg 6 h at 32 weeks, 30 mg/kg 6 h at 36 weeks and 20 mg/kg 4 h at term (propacetamol doses). Since the role of the oxidative enzyme CYP2E1 and production of the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine still is unknown in premature neonates, lower doses scaled by age-related clearance and centred on a daily dose of 60 mg/kg per day in a child of 6-8 years with a clearance of 0.25 l/h per kg (12.5 l/h per 70 kg) may be more appropriate.
Allegaert
Karel
K
Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
Anderson
Brian J
BJ
Naulaers
Gunnar
G
de Hoon
Jan
J
Verbesselt
Rene
R
Debeer
Anne
A
Devlieger
Hugo
H
Tibboel
Dick
D
D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D000367:Age Factors; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001835:Body Weight; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; C063776:propacetamol