Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model

Abstract

<b><i>Background:</i></b> Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. <b><i>Methods:</i></b> Twelve fetal lambs (127–133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored. <b><i>Results:</i></b> The transplacental sildenafil transfer was 2.9% (range: 1.4–7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38–78%) and increased both pulmonary blood flow (32–132%) and heart rate (13–49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion. <b><i>Conclusion:</i></b> In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.

MRI Characterization of Blood Flow and Oxygen Delivery in the Fetal Sheep whilst Exposed to Sildenafil Citrate

“…Fetal mean arterial pressure and HR were not different during the basal and SC MRI acquisition windows. Given that SC can transiently alter fetal blood pressure [25], we began MRI acquisitions 15 min after the onset of fetal SC exposure in an attempt to avoid any potential transient haemodynamic instability. Unlike recent findings by De Bie et al [25], we found no impact of SC on blood pressure, transient or otherwise.…”

“…Given that SC can transiently alter fetal blood pressure [25], we began MRI acquisitions 15 min after the onset of fetal SC exposure in an attempt to avoid any potential transient haemodynamic instability. Unlike recent findings by De Bie et al [25], we found no impact of SC on blood pressure, transient or otherwise. It should be noted that fetal SC exposure during the STRIDER trials occurred over a chronic timeframe and thus acute transient alterations to fetal blood pressure or HR at the onset of SC exposure are unlikely to impact longer-term cardiovascular outcomes.…”

“…The SC dosing regime in the present study targeted fetal sheep plasma SC concentrations after SC doses equivalent to those administered in the STRIDER trial were given to pregnant ewes [18, 37]. However, the capacity for SC to cross the sheep placenta appears to be limited [25] with an ex vivo dually perfused human cotyledon model suggesting that the transfer capacity of SC across the human placenta may be more efficient [39]. This would result in the human fetus being exposed to a higher concentration of SC during the STRIDER trials than the fetal sheep in this study were exposed to during the MRI acquisitions.…”

PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia

“…Interestingly, the two sheep studies in this field have both demonstrated effects of sildenafil at fetal concentrations well below the currently used therapeutic range. Both an acute pulmonary vasodilatory effect ( de Bie et al, 2021b ) and an effect on neonatal cardiopulmonary hemodynamics (suggesting a longer-term effect on pulmonary vascular development) ( Kashyap et al, 2019 ) were observed at concentrations that are currently assumed to be ‘subtherapeutic’. It is therefore possible that the required fetal sildenafil concentration to achieve the desired developmental effect is lower than the concentration required to achieve acute vasodilation in neonates.…”

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

“…In a fetal lamb model with CDH, prenatal sildenafil exposure reduced pulmonary arterial pressure and increased pulmonary blood flow after birth, resulting in improved gas exchange [ 113 ]. However, the transplacental transfer of sildenafil to the fetal compartment in sheep was later shown to be very minimal [ 114 ]. This is tied to this animal model.…”