Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

Abstract

Background and Objective Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal-maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi ® ]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

“…A number of PBPK models that have been verified for maternalfetal transfer of drug are available and may assist in risk-benefit assessments of drug treatment. [186][187][188] Furthermore, PBPK models that have been verified for lactation can also help predict potential neonatal/infant exposures to drugs and be weighed against findings in toxicology studies.…”

Model‐Informed Dose Optimization in Pregnancy

“…The values predicted by incorporating data from ex vivo cotyledon perfusion experiments in the model were in line with the observed cord blood data. 56 An existing p-PBPK model for acetaminophen was modified by Mian et al 65 to incorporate a fetal component. The placental transfer was evaluated by either ex vivo cotyledon perfusion experiments or scaling based on Caco-2 cell permeability experiments, physicochemical properties in MoBi.…”

“…An existing p‐PBPK model for acetaminophen was modified by Mian et al 65 to incorporate a fetal component. The placental transfer was evaluated by either ex vivo cotyledon perfusion experiments or scaling based on Caco‐2 cell permeability experiments, physicochemical properties in MoBi.…”

Acetaminophen Use in Pregnant Women and Their Neonates: Safe or Unsafe till Proven Otherwise?

“…Lastly, we would like to advocate using appropriate dosing of acetaminophen in pregnant women and their newborns as we still consider this as a “real” drug with effects and potential side effects [18, 19]. This suggestion is in line with a recently revised summary of product characteristics (the leaflet) for acetaminophen by the European Medicine Agency.…”

“…We would like to conclude that at this moment there is no reason to discontinue the use of acetaminophen in pregnant women and their neonates because the alternative, the use of opioids, has proven to result in a dramatic increase in opioid-addicted neonates across many countries worldwide, while exposure to other nonsteroidal anti-inflammatory drugs like ibuprofen or indomethacin is associated with a much higher risk for fetal ductal closure when compared to acetaminophen [17]. Lastly, we would like to advocate using appropriate dosing of acetaminophen in pregnant women and their newborns as we still consider this as a "real" drug with effects and potential side effects [18,19]. This suggestion is in line with a recently revised summary of product characteristics (the leaflet) for acetaminophen by the European Medicine Agency.…”