Mechanism Of Action
Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment
(Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding
affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.
In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced
to below the lower limit of quantification immediately after the administration of 5 g idarucizumab.
SubjectsÃ¢â¬™ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time
(ACT) parameters returned to baseline levels (see Figure 4 and Figure 5). This reduction of dabigatran
plasma concentration was observed over the entire observation period of at least 24 hours. Similar
findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and
moderate renal impairment [see Pharmacokinetics].
In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to reelevation
of dTT, ECT, aPTT, and TT [see WARNINGS AND PRECAUTIONS].
Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first
infusion revealed no differences in safety and no indication of allergic reactions [see Pharmacokinetics].
No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation
24 hours after the administration of idarucizumab [see DOSAGE AND ADMINISTRATION].
Figure 4 Plasma-Levels of Unbound Dabigatran in the Representative Group of Healthy Subjects (Administration of Idarucizumab or Placebo at 0 h)
Figure 5 Change of ECT from Baseline in the Representative Group of Healthy Subjects (Administration of Idarucizumab or Placebo at 0h)
Thrombin Generation Parameters
Idarucizumab alone has shown no procoagulant effect measured as endogenous thrombin potential
Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG)
parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals). There were
no clinically relevant abnormal findings related to ECG.
In Vitro Assessment Of Drug Interactions
In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation
factor concentrates [3- or 4-factor prothrombin complex concentrates (PCCs), activated PCC, or
recombinant Factor VIIa].
Assessment Of Drug Interactions In Animal Studies
The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement
agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in
swine. The results of this study suggest that neutralization of dabigatran anticoagulant activity is not
influenced by 50% hemodilution with routinely used volume replacement strategies.
There were no obvious differences in the idarucizumab plasma concentration time profiles when
idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase
in the fraction of unchanged idarucizumab excreted in urine was observed.
Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution.
Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady
state (Vss ) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).
Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial halflife
of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous
administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a
collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose
is assumed to be eliminated via protein catabolism, mainly in the kidney.
Several pathways have been described that may contribute to the metabolism of antibodies. All of these
pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino
acids which are then reabsorbed and incorporated in the general protein synthesis.
Age, Sex, Race And Body Weight
Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic
exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort
of 201 males and 19 females.
Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance ≥60 to
<90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (creatinine
clearance ≥30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading
to an increase in idarucizumabÃ¢â¬™s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate
renal impairment, respectively [see Use In Specific Populations].
The safety and effectiveness of PRAXBIND has been investigated in
pharmacokinetic/pharmacodynamic trials with healthy volunteers and in an ongoing single cohort case
series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who
require emergency surgery or urgent procedure (RE-VERSE AD).
Three randomized, placebo-controlled trials in a total of 283 subjects assessed the safety, doseresponse,
and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of
the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and
30 subjects aged 65 years or older (median age 36 years).
The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT,
and ACT over time for 14 subjects treated in one of the healthy volunteer trials. Fourteen subjects
received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of
dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as
one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment
group and Table 2 shows the results of the placebo treatment group.
Table 1: Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects Treated with 5 g
(Mean and Standard
|End of infusion of Idarucizumab
|24 hours after
Table 2: Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects
Treated with Placebo
(Mean and Standard Deviation)
|End of infusion of Placebo
|24 hours after
The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized under
section in Pharmacodynamics.
RE-VERSE AD Patient Experience
In an ongoing single cohort case series trial, 5 g idarucizumab was administered to patients treated with
dabigatran 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 pharmacodynamic anticoagulant effect of dabigatran within 4 hours
after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.
An interim analysis of the ongoing single cohort case series trial included data for 123 patients: 66
patients with serious bleeding (Group A) and 57 requiring an urgent procedure (Group B).
Approximately half of the patients in each group were male. The median age was 77 years and the
median creatinine clearance was 55 mL/min. Approximately 67% of patients in Group A and 63% of
patients in Group B had been treated with dabigatran 110 mg BID. Results of central laboratory
evaluations were available for a subset of 90 patients (51 in Group A, 39 in Group B).
Among the 90 patients with available data, the median maximum reversal of the pharmacodynamic
anticoagulant effect of dabigatran as measured by ECT or dTT in the first 4 hours after administration
of 5 g idarucizumab was 100%, with most patients (>89%) achieving complete reversal. Reversal of the
pharmacodynamics effects was evident immediately after administration. Results for Groups A and B
were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g
idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. ECT
measures over the 24-hour observation time are shown in Figure 6.
Figure 6: Change of ECT from Baseline in 90 Dabigatran-exposed Patients
Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7).
Figure 7: Change of aPTT from Baseline in 90 Dabigatran-exposed Patients