Physiologically based pharmacokinetic modelling of acetaminophen in preterm neonates—The impact of metabolising enzyme ontogeny and reduced cardiac output

Olusola Olafuyi*, Mohammad Yaseen Abbasi, Karel Allegaert

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)
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Abstract

In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on the pharmacokinetics of APAP in preterm neonates and to study the effect of reduced cardiac output (CO) on its PK using PBPK modelling. A PBPK model for APAP was first developed and validated in adults and then scaled to paediatric age groups to account for the effect of enzyme ontogeny. In preterm neonates, CO was reduced by 10%, 20%, and 30% to determine how this might affect APAP PK in preterm neonates. In all age groups, the predicted concentration-time profiles of APAP were within 5th and 95th percentile of the clinically observed concentration-time profiles and the predicted Cmax and AUC were within 2-folds of the reported parameters in clinical studies. Sulfation accounted for most of APAP metabolism in children, with the highest contribution of 68% in preterm neonates. A reduction in CO by up to 30% did not significantly alter the clearance of APAP in preterm neonates. The model successfully incorporated the ontogeny of drug metabolising enzymes involved in APAP metabolism and adequately predicted the PK of APAP in preterm neonates. A reduction in hepatic perfusion as a result of up to 30% reduction in CO has no effect on the PK of APAP in preterm neonates.

Original languageEnglish
Pages (from-to)401-417
Number of pages17
JournalBiopharmaceutics and Drug Disposition
Volume42
Issue number9
Early online date18 Aug 2021
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

ACKNOWLEDGEMENTS:
The authors would like to thank Certara (Simcyp ?) for providing the academic license to conduct the study. They would also like to thank Mian Zhang (Certara) for the extra support provided during this work.

Publisher Copyright:
© 2021 John Wiley & Sons Ltd.

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