Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.
Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.
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DOI：
10.1124/dmd.121.000648
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发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Chiba, Koji
中科院分区：
文献类型：
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作者：
Kurosawa, Ken;Noguchi, Saki;Chiba, Koji
地高辛被用作治疗胎儿室上性心动过速的一线治疗;然而，由于治疗窗较窄，因此必须估计胎儿中地高辛的暴露量。离体人胎盘灌注研究的数据用于无创预测体内胎儿暴露，但在地高辛灌注研究中观察到的离体胎儿与母体浓度（F：M）比远低于体内。在本研究中，我们开发了一个人经胎盘地高辛的药代动力学模型，使用以前报道的离体人胎盘灌注数据。该模型由母体绒毛间、胎儿毛细血管、非灌注组织和合体滋养层隔室组成，其中多药耐药蛋白（MDR）1和微绒毛膜（MVM）处的流入转运蛋白以及基底质膜（BM）处的流入和流出转运蛋白。模型预测的F：M比为0.66，与体内平均值0.77一致（95%置信区间：0.64-0.91）。离体灌注研究达到稳态的时间估计为1，500分钟，这比报告的离体实验持续时间长得多，认为该差异是离体和体内F：M比之间不一致的原因。在与MDR 1抑制剂奎尼丁和维拉帕米的药物相互作用研究中报告的地高辛浓度与我们的模型模拟的曲线一致，该模型除MVM外还包括BM外排转运蛋白的抑制。我们的建模和模拟方法应该是一个强大的工具，预测胎儿暴露和人体胎盘中的DDI。重要性声明：我们开发了一个人经胎盘地高辛的药代动力学模型的基础上离体人胎盘灌注研究，以解决报告的离体和体内胎儿-母体浓度比之间的不一致。该模型成功地预测了地高辛的体内胎儿暴露和地高辛和P-糖蛋白/多药耐药蛋白1抑制剂在人胎盘中的药物相互作用。
Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT: We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.