Link: https://www.ncbi.nlm.nih.gov/pubmed/30194048

Am J Obstet Gynecol. 2018 Sep 4. pii: S0002-9378(130720-8. doi: 10.1016/j.ajog.2018.08.041. [Epub ahead of print]
Sildenafil crosses the placenta at therapeutic levels in a dually perfused human cotyledon model.
Russo FM1, Conings S2, Allegaert K3, van Mieghem T4, Toelen J2, van Calsteren K1, Annaert P5, Deprest J6.
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Abstract
BACKGROUND:
Sildenafil is already administered during gestation in patients with pulmonary hypertension and is under evaluation as a treatment for several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction. Animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature and airway phenotype. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required.

OBJECTIVE:
We quantified transplacental passage of sildenafil in the ex vivo dually perfused cotyledon model.

STUDY DESIGN:
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, representing the maximum tolerated concentration (N=3) and 50 ng/mL, representing the therapeutic concentration (N=3). Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150 and 180 minutes, and the concentrations of sildenafil and its metabolite desmethyl-sildenafil were determined using high performance liquid chromatography. The fetal/maternal concentration ratio was calculated for each time-point. Transfer clearance was calculated as the rate of maternal to fetal passage/maternal concentration.

RESULTS:
Sildenafil crossed the placenta at both maximal and therapeutic concentrations. Maternal and fetal levels reached a plateau at 90-120 minutes. Transfer clearance was the highest during the first hour of perfusion, being 3.15 (range 2.14-3.19) mL/min for the maximum tolerated concentration and 3.07 (range 2.75-3.42) mL/min for the therapeutic concentration (NS). The feto-maternal concentration ratio significantly increased over time, up to 0.91 ± 0.16 for the maximal concentration and 0.95 ± 0.22 for the therapeutic concentration at the end of the perfusion (NS). Desmethyl-sildenafil was not detected in any sample.

CONCLUSION:
Sildenafil crosses the term placenta at a relatively high rate ex vivo, suggesting that there is sufficient placental transfer to reach clinically active fetal drug levels at the currently used maternal doses.

Copyright © 2018. Published by Elsevier Inc.