Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models
Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models
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DOI：
10.1111/bcp.12815
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发表时间：
2016-04-01
影响因子：
3.4
通讯作者：
Benaboud, Sihem
中科院分区：
文献类型：
--
作者：
Mendes, Mailys De Sousa;Hirt, Deborah;Benaboud, Sihem
孕妇在怀孕期间可能接触到许多药物。由于明显的伦理原因，胎儿暴露于药物的体内研究有限。关于孕妇用药前药物经胎盘转移的信息将非常有用。在本研究中，开发了一种新的方法，定量预测或预测胎儿暴露于药物管理的motherquantitatives. Methodstransplantatory参数估计从离体人胎盘灌注实验中实施妊娠生理为基础的药代动力学（p-PBPK）模型，以预测胎儿PK。此后，模拟了两种抗逆转录病毒药物替诺福韦（TFV）和恩曲他滨（FTC）的胎儿PK曲线。然后，这些预测进行比较，观察到的脐带血浓度，以验证这些models.ResultsParameters从体外实验中获得的，使一个很好的预测所观察到的脐带血浓度，而无需额外的缩放因子。此外，敏感性分析表明，胎儿的预测是敏感的transplacental参数值的变化获得exvivo.ConclusionThe整合的p-PBPK模型中的离体人胎盘灌注参数预测人类胎儿暴露于外源性物质应该是一个有前途的新方法。
AIMSPregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively.MethodsTransplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models.ResultsParameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo.ConclusionThe integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.