BACKGROUND: The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates. METHODS: A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27-45 weeks' postmenstrual age (PMA)) was undertaken using non-linear mixed effects models. Data from three published studies were pooled with newly collected time-concentration points during repeated intravenous paracetamol administration. RESULTS: A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%. CONCLUSIONS: Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32-44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential.
BACKGROUND: The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates. METHODS: A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27-45 weeks' postmenstrual age (PMA)) was undertaken using non-linear mixed effects models. Data from three published studies were pooled with newly collected time-concentration points during repeated intravenous paracetamol administration. RESULTS: A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%. CONCLUSIONS:Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32-44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential.
Authors: Manfred Hauben; Stephen Bai; Eric Hung; Kasia Lobello; Charles Tressler; Vincent P Zucal Journal: Eur J Clin Pharmacol Date: 2021-01-07 Impact factor: 2.953
Authors: Wojciech Krzyzanski; Sarah F Cook; Melanie Wilbaux; Catherine M T Sherwin; Karel Allegaert; An Vermeulen; John N van den Anker Journal: AAPS J Date: 2019-05-28 Impact factor: 4.009
Authors: Anne Smits; Rene Verbesselt; Aida Kulo; Gunnar Naulaers; Jan de Hoon; Karel Allegaert Journal: Eur J Drug Metab Pharmacokinet Date: 2012-11-17 Impact factor: 2.441
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