Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Nov;42(9):401-417.
doi: 10.1002/bdd.2301. Epub 2021 Aug 28.

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

Olusola Olafuyi  1 , Mohammad Yaseen Abbasi  2 , Karel Allegaert  3   4   5
Affiliations

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

Olusola Olafuyi et al. Biopharm Drug Dispos. 2021 Nov.

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.

Keywords: Preterm neonates; acetaminophen; cardiac output; ontogeny; physiologically based pharmacokinetics.

PubMed Disclaimer

References

REFERENCES

    1. Abduljalil, K., Pan, X., Pansari, A., Jamei, M., & Johnson, T. N. (2020a). A preterm physiologically based pharmacokinetic model. Part I: Physiological parameters and model building. Clinical Pharmacokinetics, 59(4), 485-500. https://doi.org/10.1007/s40262-019-00825-6
    1. Abduljalil, K., Pan, X., Pansari, A., Jamei, M., & Johnson, T. N. (2020b). Preterm physiologically based pharmacokinetic model. Part II: Applications of the model to predict drug pharmacokinetics in the preterm population. Clinical Pharmacokinetics, 59(4), 501-518. https://doi.org/10.1007/s40262-019-00827-4
    1. Adiwidjaja, J., Boddy, A. V., & McLachlan, A. J. (2020). Implementation of a physiologically based pharmacokinetic modeling approach to guide optimal dosing regimens for imatinib and potential drug interactions in paediatrics. Frontiers in Pharmacology, 10, ARTN 1672. https://doi.org/10.3389/fphar.2019.01672
    1. Adjei, A. A., Gaedigk, A., Simon, S. D., Weinshilboum, R. M., & Leeder, J. S. (2008). Interindividual variability in acetaminophen sulfation by human fetal liver: Implications for pharmacogenetic investigations of drug-induced birth defects. Birth Defects Research Part A-Clinical and Molecular Teratology, 82(3), 155-165. https://doi.org/10.1002/bdra.20535
    1. Allegaert, K., Naulaers, G., Vanhaesebrouck, S., & Anderson, B. J. (2013). The paracetamol concentration-effect relation in neonates. Paediatric Anaesthesia, 23(1), 45-50. https://doi.org/10.1111/pan.12076

LinkOut - more resources