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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 11/2016

01-11-2016 | Original Research Article

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

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

Published in: Clinical Pharmacokinetics | Issue 11/2016

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Abstract

Objectives

This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites.

Methods

Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks’ gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks’ gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration–time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2.

Results

The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038–0.062; 62 %) for glucuronidation, 0.21 L/h (0.17–0.24; 33 %) for sulfation, and 0.058 L/h (0.044–0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age.

Conclusions

The parent–metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.
Appendix
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Metadata
Title
Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model
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
Publication date
01-11-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 11/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0408-1

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