Yunan Yan, Qiushi Wang, Wei Wu, Hanxi Yi, Feifan Xie
{"title":"评估万古霉素经胎盘清除率的各种方法，利用母胎生理药代动力学模型预测胎儿浓度","authors":"Yunan Yan, Qiushi Wang, Wei Wu, Hanxi Yi, Feifan Xie","doi":"10.1007/s11095-024-03705-2","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. <i>Ex vivo</i> human placenta perfusion experiments are the most suitable approach for this assessment. Various <i>in silico</i> 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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p><i>Ex vivo</i> human placenta perfusion experiments, <i>in silico</i> approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability <i>in vitro-in vivo</i> correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CL<sub>PD</sub>) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CL<sub>PD</sub> values as a crucial input parameter for transplacental kinetics.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CL<sub>PD</sub> parameterization derived from <i>ex vivo</i> 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 CL<sub>PD</sub> parameter was derived from alternative prediction methods, none of the extrapolated maternal–fetal PBPK models produced fetal predictions in line with the observed data.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Our study showcased that combination of <i>ex vivo</i> 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 <i>in silico</i> approaches failed to achieve the same level of accuracy.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal–Fetal Physiologically Based Pharmacokinetic Model\",\"authors\":\"Yunan Yan, Qiushi Wang, Wei Wu, Hanxi Yi, Feifan Xie\",\"doi\":\"10.1007/s11095-024-03705-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background</h3><p>Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. <i>Ex vivo</i> human placenta perfusion experiments are the most suitable approach for this assessment. Various <i>in silico</i> 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.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p><i>Ex vivo</i> human placenta perfusion experiments, <i>in silico</i> approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability <i>in vitro-in vivo</i> correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CL<sub>PD</sub>) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CL<sub>PD</sub> values as a crucial input parameter for transplacental kinetics.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CL<sub>PD</sub> parameterization derived from <i>ex vivo</i> 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. 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Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal–Fetal Physiologically Based Pharmacokinetic Model
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.
Conclusion
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.
期刊介绍：
Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to:
-(pre)formulation engineering and processing-
computational biopharmaceutics-
drug delivery and targeting-
molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)-
pharmacokinetics, pharmacodynamics and pharmacogenetics.
Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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