Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery.

Paola Mian,Karel Allegaert,Kristel van Calsteren,Bridget Nolan,John N. van den Anker,André Dallmann,Nisha Lakhi

doi:10.3389/fped.2021.733520

Abstract

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

Highlights

Despite frequent and increasing drug use in pregnant women [1, 2], little is known about placental drug transfer and pharmacokinetics in the fetus
We developed a novel in silico cotyledon perfusion model that is structurally equivalent with the placenta implemented in the physiologically based pharmacokinetic (PBPK) model
The fitted value ± 95% confidence interval for the placental partition coefficients, KFM_cell : perf and KF_cell : perf, was 4.31 ± 0.57 [vs. 0.76 when being estimating according to the method described by Rodgers et al [30, 31]] resulting in a substantial amount of acetaminophen accumulating in the trophoblasts of the cotyledon

Summary

Introduction

Despite frequent and increasing drug use in pregnant women [1, 2], little is known about placental drug transfer and pharmacokinetics in the fetus. The kinetic in silico models representing the ex vivo cotyledon perfusion system typically consist of few compartments and lump various tissue portions of the cotyledon, e.g., intravillous vascular, interstitial, and intracellular space, in a single compartment. In general these models appear to scale well with the placental drug transfer kinetics simulated in whole-body models, the relatively simple structure prevents a more mechanistic understanding of the transfer kinetics. Tissue-specific pharmacology of a given drug within the placenta and potential interactions with its endocrine synthesis and secretion of hormones (e.g., prostaglandins) may affect fetal development and pregnancy outcome (e.g., preterm induction of labor)

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