Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution

• Published in: PloS one 2019-01, Vol.14 (1), p.e0209350-e0209350
• Main Authors: Grottke, Oliver, van Ryn, Joanne, Zentai, Christian, Gan, Guanfa, Honickel, Markus, Rossaint, Rolf, Ten Cate, Hugo, Spronk, Henri M H
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - pharmacokinetics; Anticoagulants; Antidotes - pharmacokinetics; Antithrombins - blood; Antithrombins - pharmacokinetics; Binding; Biology and Life Sciences; Blood; Blood Coagulation Disorders - blood; Blood Coagulation Disorders - therapy; Blood volume; Blood Volume - physiology; Coagulation; Dabigatran - antagonists & inhibitors; Dabigatran - blood; Dabigatran - pharmacokinetics; Dilution; Dosage and administration; Drug therapy; Expanders; Gelatin; Health aspects; Hemodilution; Hemorrhage; Hemorrhagic shock; Hydroxyethyl starch; Idarucizumab; Laboratories; Male; Mathematical models; Medicine and Health Sciences; Models, Animal; Monoclonal antibodies; Mortality; Parameters; Plasma Substitutes - administration & dosage; Plasma Substitutes - metabolism; Prolongation; Research and Analysis Methods; Resuscitation; Starch; Sus scrofa; Swine; Systematic review; Thrombin; Trauma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0209350

Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer's solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.