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.
|Keywords||Neonate, Paracetamol, Propacetamol|
|Persistent URL||dx.doi.org/10.1007/s00228-004-0756-x, hdl.handle.net/1765/68310|
|Journal||European Journal of Clinical Pharmacology|
Allegaert, K.M, Anderson, B.J, Naulaers, G, de Hoon, J.N, Verbesselt, R, Debeer, A, … Tibboel, D. (2004). Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. European Journal of Clinical Pharmacology, 60(3), 191–197. doi:10.1007/s00228-004-0756-x