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.
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.
Authors: Karel Allegaert; Dick Tibboel; Gunnar Naulaers; Denise Tison; Annick De Jonge; Monique Van Dijk; Christine Vanhole; Hugo Devlieger Journal: Eur J Clin Pharmacol Date: 2003-04-04 Impact factor: 2.953
Authors: Brian J Anderson; Richard A van Lingen; Tom G Hansen; Yuan-Chi Lin; Nicholas H G Holford Journal: Anesthesiology Date: 2002-06 Impact factor: 7.892
Authors: Caroline D van der Marel; Brian J Anderson; Richard A van Lingen; Nicholas H G Holford; Marien A L Pluim; Frank G A Jansman; John N van den Anker; Dick Tibboel Journal: Eur J Clin Pharmacol Date: 2003-05-22 Impact factor: 2.953
Authors: M Depré; A van Hecken; R Verbesselt; T B Tjandra-Maga; M Gerin; P J de Schepper Journal: Fundam Clin Pharmacol Date: 1992 Impact factor: 2.748
Authors: Matthew W Linakis; Sarah F Cook; Shaun S Kumar; Xiaoxi Liu; Diana G Wilkins; Roger Gaedigk; Andrea Gaedigk; Catherine M T Sherwin; John N van den Anker Journal: Clin Pharmacokinet Date: 2018-10 Impact factor: 6.447
Authors: Gudrun Würthwein; Susanne Koling; Alexander Reich; Georg Hempel; Petra Schulze-Westhoff; Paulo V Pinheiro; Joachim Boos Journal: Eur J Clin Pharmacol Date: 2005-01-21 Impact factor: 2.953
Authors: Aida Kulo; Mariska Y Peeters; Karel Allegaert; Anne Smits; Jan de Hoon; Rene Verbesselt; Liesbeth Lewi; Marc van de Velde; Catherijne A J Knibbe Journal: Br J Clin Pharmacol Date: 2013-03 Impact factor: 4.335
Authors: Sarah F Cook; Chris Stockmann; Samira Samiee-Zafarghandy; Amber D King; Nina Deutsch; Elaine F Williams; Diana G Wilkins; Catherine M T Sherwin; John N van den Anker Journal: Clin Pharmacokinet Date: 2016-11 Impact factor: 6.447