Publications

22 novembre 2024
Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment

Clin Pharmacokinet. 2024 Dec;63(12):1689-1700. doi: 10.1007/s40262-024-01439-3. Epub 2024 Nov 22.

Faheemah Padavia 1 , Jean-Marc Treluyer 2 3 4 5 , Gilles Cambonie 6 7 , Cyril Flamant 8 , Aline Rideau 9 , Manon Tauzin 10 , Juliana Patkai 11 , Géraldine Gascoin 12 , Mirka Lumia 13 , Outi Aikio 14 , Frantz Foissac 2 3 4 , Saïk Urien 2 3 4 , Sihem Benaboud 2 5 , Gabrielle Lui 2 5 , Léo Froelicher Bournaud 2 5 , Yi Zheng 5 , Ruth Kemper 15 , Marine Tortigue 16 17 18 , Alban-Elouen Baruteau 16 17 18 19 , Jaana Kallio 13 , Mikko Hallman 14 , Alpha Diallo 20 21 , Léa Levoyer 20 21 , Jean-Christophe Roze 18 19 , Naïm Bouazza 2 3 4
PMID: 39578300 PMCID: PMC11649743 DOI: 10.1007/s40262-024-01439-3

Abstract

Aims: Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated.

Methods: Preterm neonates of 23-26 weeks’ gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage.

Results: Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures.

Conclusion: The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure.

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