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.

Fig. 1

Schematic workflow of fetal–maternal physiologically based pharmacokinetic (f-m PBPK) model development and evaluation. D_cot transcotyledon passive diffusion clearance, D_pl transplacental passive diffusion clearance, K_f,m partition coefficient between the fetal and maternal compartment, PBPK physiologically based pharmacokinetic, PK pharmacokinetics

Fig. 2

Structure of the fetal–maternal physiologically based pharmacokinetic (f-m PBPK) model. The four sub-compartments (blood cells, plasma, interstitial, and intracellular) for acetaminophen distribution in the fetal liver have been visualized separately. Solid lines and closed arrows indicate blood flow process, dash–dotted lines and closed arrows indicate biliary secretion or movement along the intestine through gastrointestinal motility, solid lines and open arrows indicate transport across the placenta through passive diffusion, boxes with solid frame indicate compartments representing organs available in both non-pregnant and pregnant women, and boxes with dashed frame indicate compartments representing organs exclusively available in pregnant women

Fig. 3

Schematic representation of the ex vivo cotyledon perfusion model. D_cot transcotyledon passive diffusion clearance, K_f,m partition coefficient between the fetal and maternal compartment, K_pe placental elimination, Q_f fetal flow rate, Q_m maternal flow rate, V_f volume of fetal reservoir, V_m volume of maternal reservoir, V_fp volume of fetal part of the cotyledon, V_mp volume of maternal part of cotyledon

Fig. 4

Ex vivo observed [19] fetal and maternal acetaminophen concentration compared with fetal and maternal simulated acetaminophen profiles in the ex vivo cotyledon perfusion experiment

Fig. 5

Predicted maternal (a) and fetal (b) acetaminophen pharmacokinetic profiles in venous umbilical cord plasma following administration of oral acetaminophen 1000 mg using the three different placental transfer approaches described in the text. Predicted maternal and fetal plasma acetaminophen pharmacokinetic profiles were compared with observed cord blood concentrations for the maternal dose of 1000 mg [19]

Fig. 6

Bar graph of the predicted median fractions of metabolite formation from acetaminophen (expressed as percentage of molar acetaminophen dose) for a fetus at term (a) and a mean individual pregnant woman at term (b). NAPQI N-acetyl-p-benzoquinone imine

Fig. 7

Sensitivity analyses illustrating how the predicted fetal acetaminophen concentrations responds to variations in either the transplacental passive diffusion clearance (D_pl) or partition coefficient between the fetal and maternal compartment (K_f,m). The parameter values for these two parameters were calculated from the three evaluated approaches: ex vivo cotyledon perfusion experiment (a, b), scaling of placental transfer rate via physicochemical properties (MoBi^® default method) (c, d), and scaling of placental transfer rate via Caco-2 cell permeability (e, f)