474: Placenta transfer of sildenafil citrate in the ex-vivo human cotyledon perfusion model

Abstract

Sildenafil is currently being administered to pregnant patients with pulmonary hypertension and is under evaluation as a treatment for several placental complications, such as pre-eclampsia and intrauterine growth restriction. Since animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature and airway complexity. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required. Herein we aimed to measure transplacental transfer of sildenafil using the ex-vivo human placental perfusion model. Six placentas were collected after term delivery from healthy volunteers, cannulated and dually perfused. Sildenafil citrate was added to the maternal circulation at two different concentrations: 500 ng/mL (N=3) and 50 ng/mL (N=3), representing the maximal tolerated concentration (MC) and the therapeutic concentration (TC), respectively. Anti-pyrine (AP) 100ug/mL was also added to the maternal reservoir and used as internal control. Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150 and 180 min, and the concentration of sildenafil and its metabolite desmethyl (DM)-sildenafil was determined using high performance liquid chromatography. Feto-maternal (FM) ratio (fetal/maternal concentration) and normalized FM ratio (sildenafil FM ratio/AP FM ratio) were calculated for each time-point. Transfer clearance was calculated as the rate of fetal excretion/maternal concentration. Sildenafil crossed the placenta at both concentrations. Both maternal and fetal levels reached a plateau at 90-120 min. Median transfer clearance during the first two hours was 1.20 (IQR 0.50) mL/min for MC and 1.43 (IQR 0.31) mL/min for TC. At steady state (180 min), the median FM ratio was 0.94 (IQR 0.21) and 1.15 (IQR 0.11), and the median normalized FM ratio was 1 (IQR 0.21) and 1.24 (IQR 0.05) for MC and TC respectively (Figure 1). DM-sildenafil was not detected in any sample. Sildenafil crosses the term placenta at a relatively high rate ex-vivo, suggesting that there is sufficient placental transfer to reach therapeutic fetal drug levels at non-toxic maternal dose.