PBPK modeling of intravenous/oral acetaminophen in healthy and pregnant individuals

Abstract: Background: Drug metabolism may be influenced by pregnancy. Use of acetaminophen (APAP) is prevalent among pregnant women, necessitating the development of effective methods for predicting its in-vivo disposition. Objectives: A whole physiologically based pharmacokinetic model was developed to predict the pharmacokinetic behavior of APAP following oral or intravenous administration in both healthy subjects and pregnant women across different trimesters (first, second, and third trimesters). Methods: Phoenix WinNonlin 8.4 was used to establish the model, which was verified by literature data and the fold error method. Sensitivity analysis was used to identify the factors most sensitive to the model results. Results: The model was established successfully. The clearance rate and half-life of intravenous APAP increased during pregnancy and the changes were more obvious with the increase of pregnancy trimesters. Theoretically, adjusting the oral and intravenous doses for pregnant women in the third trimester to 1.23 and 1.16 times those administered to healthy individuals may yield a comparable area under the curve in healthy subjects. According to the sensitivity analysis results, the influencing factors were ranked from largest to smallest as follows: activity of sulfatase > activity of glucuronidase > the constant of the gastrointestinal transport rate > activity of CYP450. Conclusion: Pregnancy affects the metabolism of APAP and more attention should be paid to pregnant women in clinical medication.