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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 1/2016

01-01-2016 | Original Research Article

Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation

Authors: Sarah F. Cook, Jessica K. Roberts, Samira Samiee-Zafarghandy, Chris Stockmann, Amber D. King, Nina Deutsch, Elaine F. Williams, Karel Allegaert, Diana G. Wilkins, Catherine M. T. Sherwin, John N. van den Anker

Published in: Clinical Pharmacokinetics | Issue 1/2016

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Abstract

Objectives

The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset.

Methods

Nonlinear mixed-effects models were constructed from paracetamol concentration–time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors.

Results

The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1–14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1–28.1).

Conclusions

Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.
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Metadata
Title
Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation
Authors
Sarah F. Cook
Jessica K. Roberts
Samira Samiee-Zafarghandy
Chris Stockmann
Amber D. King
Nina Deutsch
Elaine F. Williams
Karel Allegaert
Diana G. Wilkins
Catherine M. T. Sherwin
John N. van den Anker
Publication date
01-01-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 1/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0301-3

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