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

Bapat, Priya BMSc; Kedar, Reuven MD; Lubetsky, Angelika BSc; Matlow, Jeremy N. MSc; Aleksa, Katarina PhD; Berger, Howard MD; Koren, Gideon MD

Obstetrics & Gynecology:
doi: 10.1097/AOG.0000000000000277
Contents: Original Research
Abstract

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.

In Brief

The oral anticoagulant dabigatran and its prodrug cross the term human placenta from mother to fetus.

Author Information

Motherisk Program, Division of Clinical Pharmacology, the Hospital for Sick Children, the Departments of Pharmacology and Toxicology and Pediatrics, University of Toronto, and the Department of Obstetrics and Gynecology, St Michael's Hospital, Toronto, Ontario, Canada.

Corresponding author: Gideon Koren, MD, The Motherisk Program, Division of Clinical Pharmacology & Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada; e-mail: gkoren@sickkids.ca.

Supported by a grant from the Canadian Institutes for Health Research. Priya Bapat is supported by an Ontario Graduate Scholarship. Gideon Koren is the holder of the Ivey Chair in Molecular Toxicology, the Department of Medicine, University of Western Ontario.

Financial Disclosure The authors did not report any potential conflicts of interest.

© 2014 by The American College of Obstetricians and Gynecologists.