title: Examining the transplacental passage of apixaban using the dually perfused human placenta.
abstract: Essentials Apixaban is a novel oral anticoagulant that has not been studied in pregnant patients. Our objective was to determine the rate and extent of the placental transfer of apixaban. Apixaban rapidly crosses the ex vivo term human placenta from maternal to fetal circulation. Fetal apixaban levels in vivo are estimated to be 35-90% of the corresponding maternal levels.
  
  
  
  Background Apixaban is a novel oral anticoagulant that is increasingly being prescribed to women of reproductive age. However, information regarding its placental transfer is non-existent. Objective To determine the rate and extent of placental transfer of apixaban, using the human placenta ex vivo. Methods Placentae collected after Caesarean or vaginal delivery of healthy term infants were perfused in the respective maternal and fetal circulation. At the start of the experiment, apixaban was added to the maternal circulation at a concentration of 150 ng mL(-1) , and samples from maternal and fetal reservoirs were collected over 3 h. Results There was a rapid decline of apixaban in the maternal compartment, followed by emergence in the fetal compartment with a median fetal-to-maternal drug concentration ratio of 0.77 (interquartile range [IQR], 0.76-0.81) and fetal concentration of 39.0 ng mL(-1) (IQR, 36.8-40.6) after 3 h (n = 5). The perfusion results were subsequently adjusted to account for differences in the concentration of plasma proteins in maternal and fetal blood, as apixaban remains highly bound to albumin and alpha-1 acid glycoprotein. After the adjustment, the predicted fetal-to-maternal ratio of total (bound plus unbound) apixaban concentrations in vivo ranged from 0.35 to 0.90. Conclusions We conclude that unbound apixaban rapidly crosses from the maternal to fetal circulation. We further predict that total apixaban concentrations in cord blood in vivo are 35-90% of the corresponding maternal levels, suggesting that apixaban could have a possible adverse effect on fetal and neonatal coagulation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.|Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Bapat
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: L S R
authors.initials: LS
authors.lastname: Pinto
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Lubetsky
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Aleksa
authors.affiliation: Department of Obstetrics and Gynecology, St Michael's Hospital, Toronto, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Berger
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.|Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Ito
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000493:pharmacokinetics*; D005260:Female; D005312:Fetal Blood; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D061214:Patient Safety; D010477:Perfusion; D010920:Placenta / Q000187:drug effects*; D011247:Pregnancy; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011728:Pyridones / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: anticoagulants; maternal-fetal exchange; placenta; pregnancy; venous thrombosis