Abstract：
BACKGROUND: 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 (1449.3 g/mol), using maternal-fetal physiologically based pharmacokinetic (m-f PBPK) modeling.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：评估药物经胎盘清除对预测胎儿药物暴露至关重要。离体人胎盘灌注实验是最适合这种评估的方法。还提出了各种计算机模拟方法。本研究旨在比较这些药物经胎盘清除的预测方法，专注于大分子量药物万古霉素（1449.3g/mol），使用基于母体-胎儿生理的药代动力学（m-fPBPK）建模。
方法：离体人胎盘灌注实验，评估了使用肠通透性作为替代的计算机模拟方法（定量结构性质关系（QSPR）模型和Caco-2通透性体外-体内相关模型）和具有Caco-2缩放比例的咪达唑仑校准模型，以确定万古霉素的经胎盘清除率（CLPD）。使用Simcyp逐步开发了m-fPBPK模型，将确定的CLPD值作为经胎盘动力学的关键输入参数。
结果：开发的万古霉素用于非妊娠成年人的PBPK模型显示出出色的预测性能。通过合并来自离体人胎盘灌注实验的CLPD参数化，外推的m-fPBPK模型一致地预测了不同剂量和不同胎龄的母体和胎儿万古霉素浓度.然而,当CLPD参数来自替代预测方法时，外推的母胎PBPK模型均未产生与观察数据一致的胎儿预测.
结论：我们的研究表明，体外人胎盘灌注实验和m-fPBPK模型的组合能够预测大分子量药物万古霉素的胎儿暴露，而其他计算机模拟方法未能达到相同的精度水平。
方法：离体人胎盘灌注实验，评估了使用肠通透性作为替代的计算机模拟方法（定量结构性质关系（QSPR）模型和Caco-2通透性体外-体内相关模型）和具有Caco-2缩放比例的咪达唑仑校准模型，以确定万古霉素的经胎盘清除率（CLPD）。使用Simcyp逐步开发了m-fPBPK模型，将确定的CLPD值作为经胎盘动力学的关键输入参数。
结果：开发的万古霉素用于非妊娠成年人的PBPK模型显示出出色的预测性能。通过合并来自离体人胎盘灌注实验的CLPD参数化，外推的m-fPBPK模型一致地预测了不同剂量和不同胎龄的母体和胎儿万古霉素浓度.然而,当CLPD参数来自替代预测方法时，外推的母胎PBPK模型均未产生与观察数据一致的胎儿预测.
结论：我们的研究表明，体外人胎盘灌注实验和m-fPBPK模型的组合能够预测大分子量药物万古霉素的胎儿暴露，而其他计算机模拟方法未能达到相同的精度水平。
