Transfer of Dabigatran and Dabigatran Etexilate Mesylate Across the Dually Perfused Human Placenta

• Published in: Obstetrics and gynecology (New York. 1953) Vol. 123; no. 6; pp. 1256 - 1261
• Main Authors: Bapat, Priya, Kedar, Reuven, Lubetsky, Angelika, Matlow, Jeremy N., Aleksa, Katarina, Berger, Howard, Koren, Gideon
• Format: Journal Article
• Language: English
• Published: United States by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved 01-06-2014; by The American College of Obstetricians and Gynecologists
• Subjects: Antithrombins - pharmacokinetics; Benzimidazoles - pharmacokinetics; beta-Alanine - analogs & derivatives; beta-Alanine - pharmacokinetics; Contraindications; Dabigatran; Female; Fetus - metabolism; Humans; In Vitro Techniques; Maternal-Fetal Exchange - physiology; Perfusion; Placenta - metabolism; Pregnancy; Pregnancy Complications, Hematologic - drug therapy; Prodrugs - pharmacokinetics; Pyridines - pharmacokinetics
• ISSN: 0029-7844; 1873-233X
• DOI: 10.1097/AOG.0000000000000277

OBJECTIVE:To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure.
METHODS:Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography–tandem mass spectrometry.
RESULTS:There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29–0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15–0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges.
CONCLUSION:This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.