Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: all other therapeutic products, antidotes, ATC code: V03AB37 
Mechanism of action

Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran with very high affinity, approximately 300-fold more potent than the binding affinity of dabigatran for thrombin. The idarucizumab-dabigatran complex is characterised by a rapid on-rate and extremely slow off-rate resulting in a very stable complex. Idarucizumab potently and specifically binds to dabigatran and its metabolites and neutralises their anticoagulant effect.


Praxbind                                                                    Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                   August 2020 Clinical efficacy and safety

Three randomised, double-blind, placebo-controlled Phase I studies in 283 subjects (224 treated with idarucizumab) were conducted to assess the safety, efficacy, tolerability, pharmacokinetics and pharmacodynamics of idarucizumab, given alone or after administration of dabigatran etexilate. The investigated population consisted of healthy subjects and subjects exhibiting specific population characteristics covering age, body weight, race, sex and renal impairment. In these studies the doses of idarucizumab ranged from 20 mg to 8 g and the infusion times ranged from 5 minutes to 1 hour.

Representative values for pharmacokinetic and pharmacodynamics parameters were established on the basis of healthy subjects aged 45-64 years receiving 5 g idarucizumab (see sections 5.1 and 5.2).

One prospective, open-label, non-randomized, uncontrolled study (RE-VERSE AD) was conducted to investigate the treatment of adult patients who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dilute thrombin time (dTT) or ecarin clotting time (ECT). A key secondary endpoint was the restoration of haemostasis.

RE-VERSE AD included data for 503 patients: 301 patients with serious bleeding (Group A) and 202 patients requiring an urgent procedure/surgery (Group B). Approximately half of the patients in each group were male. The median age was 78 years and the median creatinine clearance was 52.6 mL/min. 61.5% of patients in Group A and 62.4% of patients in Group B had been treated with dabigatran 110 mg twice daily.
Reversal was only evaluable for those patients showing prolonged coagulation times prior to idarucizumab treatment. Most patients in both Groups A and B, achieved complete reversal of the anticoagulant effect of dabigatran (dTT: 98.7%; ECT: 82.2%; aPTT: 92.5% of evaluable patients, respectively) in the first 4 hours after administration of 5 g idarucizumab. Reversal effects were evident immediately after administration.


Praxbind                                                                  Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                 August 2020 Figure 1 – Reversal of dabigatran-induced clotting time prolongation determined by dTT in patients from the RE-VERSE AD study (N=487)


Praxbind                                                                  Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                 August 2020 Figure 2 – Reversal of dabigatran-induced clotting time prolongation determined by ECT in patients from the RE-VERSE AD study (N=487)


Praxbind                                                                     Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                    August 2020 Figure 3 – Reversal of dabigatran-induced clotting time prolongation determined by aPTT in patients from the RE-VERSE AD study (N=486)



Restoration of haemostasis was achieved in 80.3% of evaluable patients who had serious bleeding and normal haemostasis was observed in 93.4% of patients who required an urgent procedure.

Of the total 503 patients, 101 patients died; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities. Thrombotic events were reported in 34 patients, (23 out of the 34 patients were not on antithrombotic therapy at the time of the event) and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient. Mild symptoms of potential hypersensitivity (pyrexia, bronchospasm, hyperventilation, rash or pruritus) were reported. A causal relationship to idarucizumab could not be established.


Praxbind                                                                    Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                   August 2020 Pharmacodynamic effects

The pharmacodynamics of idarucizumab after administration of dabigatran etexilate were investigated in 141 subjects in Phase I studies, of which data for a representative subgroup of 6 healthy subjects aged 45 to 64 years receiving a dose of 5 g as intravenous infusion are presented. The median peak dabigatran exposure in the investigated healthy subjects was in the range of a twice daily administration of 150 mg dabigatran etexilate in patients.

Effect of idarucizumab on the exposure and anticoagulant activity of dabigatran 
Immediately after the administration of idarucizumab, the plasma concentrations of unbound dabigatran were reduced by more than 99 %, resulting in levels with no anticoagulant activity.

The majority of the patients showed sustained reversal of dabigatran plasma concentrations up to 12 hours (≥90%). In a subset of patients, recurrence of plasma levels of unbound dabigatran and concomitant elevation of clotting tests was observed, possibly due to re-distribution of dabigatran from the periphery.
This occurred 1-24 hours after administration of idarucizumab mainly at timepoints ≥12 hours.

Figure 4 – Plasma-levels of unbound dabigatran in the representative group of healthy subjects (administration of idarucizumab or placebo at 0 h)



Dabigatran prolongs the clotting time of coagulation markers such as diluted Thrombin Time (dTT), Thrombin Time (TT), activated Partial Thromboplastin Time (aPTT) and Ecarin Clotting Time (ECT), which provide an approximate indication of the anticoagulation intensity. A value in the normal range after administration of idarucizumab indicates that a patient is no longer anticoagulated. A value above the normal range may reflect residual active dabigatran or other clinical conditions e.g., presence of other drugs or transfusion coagulopathy. These tests were used to assess the anticoagulant effect of dabigatran. A complete and sustained reversal of dabigatran-induced clotting time prolongation was observed immediately after the idarucizumab infusion, lasting over the entire observation period of at least 24 h.


Praxbind                                                                  Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                 August 2020 Figure 5 – Reversal of dabigatran-induced clotting time prolongation determined by dTT in the representative group of healthy subjects (administration of idarucizumab or placebo at 0 h) 


Figure 6 – Reversal of dabigatran-induced clotting time prolongation determined by ECT in the representative group of healthy subjects (administration of idarucizumab or placebo at 0 h) 

Praxbind                                                                    Updated prescribing information Solution for I.V. injection/infusion 50mg/ml                                                   August 2020 Thrombin generation parameters

Dabigatran exerts pronounced effects on parameters of the endogenous thrombin potential (ETP).
Idarucizumab treatment normalised both thrombin lag time ratio and time to peak ratio to baseline levels as determined 0.5 to 12 hours after the end of the idarucizumab infusion. Idarucizumab alone has shown no procoagulant effect measured as ETP. This suggests that idarucizumab has no prothrombotic effect.

Re-administration of dabigatran etexilate

24 hours after the idarucizumab infusion, re-administration of dabigatran etexilate resulted in expected anticoagulant activity.
Immunogenicity

Serum samples from 283 subjects in phase I trials (224 volunteers treated with idarucizumab) and 501 patients were tested for antibodies to idarucizumab before and after treatment.

Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 12 % (33/283) of the phase I subjects and 3.8% (19/501) of the patients. No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed.

Treatment-emergent possibly persistent anti-idarucizumab antibodies with low titers were observed in 4 % (10/224) of the phase 1 subjects and 1.6% (8/501) of the patients suggesting a low immunogenic potential of idarucizumab. In a subgroup of 6 phase 1 subjects, idarucizumab was administered a second time, two months after the first administration. No anti-idarucizumab antibodies were detected in these subjects prior to the second administration. In one subject, treatment-emergent anti-idarucizumab antibodies were detected after the second administration. Nine patients were re-dosed with idarucizumab. All nine patients were re- dosed within 6 days after the first idarucizumab dose. None of the patients re-dosed with idarucizumab tested positive for anti-idarucizumab antibodies.

Preclinical pharmacodynamics

A trauma model in pigs was performed using a blunt liver injury after dosing with dabigatran to achieve supratherapeutic concentrations of about 10-fold of human plasma levels. Idarucizumab effectively and rapidly reversed the life-threatening bleeding within 15 min after the injection. All pigs survived at idarucizumab doses of approximately 2.5 and 5 g. Without idarucizumab, the mortality in the anticoagulated group was 100 %.

Pharmacokinetic Properties