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Open Access 01-01-2020 | Paracetamol | Original Research Article

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

Authors: Paola Mian, John N. van den Anker, Kristel van Calsteren, Pieter Annaert, Dick Tibboel, Marc Pfister, Karel Allegaert, André Dallmann

Published in: Clinical Pharmacokinetics | Issue 1/2020

Abstract

Background and Objective

Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy.

Methods

PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (C_ss,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated.

Results

PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest C_ss,avg in the third trimester (median [interquartile range]: 4.5 [3.8–5.1] mg/L), while C_ss,avg was 6.7 [5.9–7.4], 5.6 [4.7–6.3], and 4.9 [4.1–5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1–13.4%]), followed by the second (9.0% [7.5–11.0%]) and third trimester (8.2% [6.8–10.1%]), compared with non-pregnant women (7.7% [6.4–9.4%]).

Conclusion

Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.

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Title: Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women
Authors: Paola Mian
John N. van den Anker
Kristel van Calsteren
Pieter Annaert
Dick Tibboel
Marc Pfister
Karel Allegaert
André Dallmann
Publication date: 01-01-2020
Publisher: Springer International Publishing
Keywords: Paracetamol
Pharmacokinetics
Published in: Clinical Pharmacokinetics / Issue 1/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-019-00799-5

At a glance: The STEP trials

Springer Medicine

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

Abstract

Background and Objective

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusion

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