Abstract
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.
Highlights
Digoxin is a cardiac glycoside extracted from the leaves of Digitalis lanata (Tantivatana and Wright, 1958)
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
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 basal plasma membrane (BM) in addition to microvillous membrane (MVM)
Summary
Digoxin is a cardiac glycoside extracted from the leaves of Digitalis lanata (Tantivatana and Wright, 1958) It has been used for many years to treat heart disease (Ziff et al, 2015), but therapeutic drug monitoring (TDM) is recommended because of serious adverse effects resulting from even small exposure changes (Beller et al, 1971; Ragab, 2012). Hutson et al (2011) proposed a method to predict the in vivo fetal to maternal concentration (F:M) ratio from ex vivo data. Their predicted F:M ratios for twenty-four drugs were generally consistent with the in vivo F:M ratios, except for four drugs. Digoxin was one of the exceptions, with a predicted F:M ratio much lower than the in vivo ratio. Hutson et al (2011)
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