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  • O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women

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European Society for Developmental Perinatal and Paediatric Pharmacology Congress, Basel, 28–30 May 2019
Oral Presentations
O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women
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  1. P Mian1,2,
  2. JN van den Anker3,4,5,
  3. K van Calsteren6,7,
  4. P Annaert8,
  5. D Tibboel1,
  6. M Pfister2,9,
  7. K Allegaert3,11,12,
  8. A Dallmann13
  1. 1Pediatric Surgery and Intensive Care, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands
  2. 2Pediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel, Basel, Switzerland
  3. 3Pediatric Surgery and Intensive Care, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands
  4. 4Pediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel (UKBB), Basel, Switzerland
  5. 5Division of Pharmacology, Children’s National Health System, Washington DC, DC, USA
  6. 6Department of Obstetrics and Gynecology
  7. 7Department of Development and Regeneration, University Hospitals Leuven
  8. 8Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
  9. 9Pediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel (UKBB), Basel, Switzerland
  10. 10Certara LP, Princeton, NJ, United States
  11. 11Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  12. 12Department of Pediatrics, Division of Neonatology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
  13. 13Pediatric Pharmacology and Pharmacometrics Research Center, University Children's Hospital Basel (UKBB), Basel, Switzerland

Abstract

Background Little is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK 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 PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.

Results PBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).

Conclusion Risk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.

Disclosure(s) Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

https://doi.org/10.1136/archdischild-2019-esdppp.5

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