Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal-Fetal Physiologically Based Pharmacokinetic Model.

Abstract

Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. Ex vivo human placenta perfusion experiments are the most suitable approach for this assessment. Various in silico methods are also proposed. This study aims to compare these prediction methods for drug transplacental clearance, focusing on the large molecular weight drug vancomycin (1449.3g/mol), using maternal-fetal physiologically based pharmacokinetic (m-f PBPK) modeling. Ex vivo human placenta perfusion experiments, in silico approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability in vitro-in vivo correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CLPD) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CLPD values as a crucial input parameter for transplacental kinetics. The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CLPD parameterization derived from ex vivo human placenta perfusion experiments, the extrapolated m-f PBPK model consistently predicted maternal and fetal concentrations of vancomycin across diverse doses and distinct gestational ages. However, when the CLPD parameter was derived from alternative prediction methods, none of the extrapolated maternal-fetal PBPK models produced fetal predictions in line with the observed data. Our study showcased that combination of ex vivo human placenta perfusion experiments and m-f PBPK model has the capability to predict fetal exposure for the large molecular weight drug vancomycin, whereas other in silico approaches failed to achieve the same level of accuracy.