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Background: The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. Methods: Five sheep were given intravenous dabigatran 4 mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480 min, and 24 h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15 mg/kg administered 120 min after dabigatran 4 mg/kg and its effect on R-time was observed. Results: A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453 L/min/70 kg), intercompartment clearance (Q 0.268 L/min/70 kg), central volume of distribution (V1 2.94 L/70 kg), peripheral volume of distribution (V2 9.51 L/70 kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2 mg/L) eliciting half of the maximal effect (EMAX 180 min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04 min. Idarucizumab 15 mg/kg reduced R-time by approximately 5 min. Conclusions: Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25 mg/kg followed by a maintenance infusion of dabigatran 0.0175 mg/kg/min for 30 min and a subsequent infusion dabigatran 0.0075 mg/kg/min achieves a steady state target concentration of 5 mg/L in a sheep model. [ABSTRACT FROM AUTHOR]

Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eleni Arnaoutoglou reports a relationship with Bayer, CLS Behring, Astra Zeneca, and Werfen that includes consulting or advisory and speaking and lecture fees. The other author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Competing Interests: Declaration of competing interest The authors declare the following financial interests and/or personal relationships that may be considered potential competing interests: Marc Maegele reports relationships with Astra Zeneca and Bayer that include consulting or advisory and speaking and lecture fees. Maria Ntalouka declares no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.