Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

Abstract

Essentials Idarucizumab, a monoclonal antibody fragment, binds dabigatran with high affinity and specificity.In this phase 1 trial, healthy Japanese males received idarucizumab alone or with dabigatran.Idarucizumab achieved immediate, complete and sustained reversal of dabigatran anticoagulation.Idarucizumab was well tolerated and demonstrated no pro‐coagulant effects. BackgroundIdarucizumab is a humanized monoclonal antibody fragment that specifically binds with high affinity to dabigatran.ObjectivesThis study investigated the safety, tolerability and pharmacokinetics of idarucizumab alone and with dabigatran at steady state, and the effects of idarucizumab on dabigatran‐induced anticoagulation.Patients/MethodsThis was a two‐part, phase I, randomized, placebo‐controlled, double‐blind, rising‐dose trial in healthy Japanese males. Part 1: 32 subjects (males) received single idarucizumab doses (1, 2, 4 or 8 g [n=6/dose group]) or placebo (n=2/dose group). Part 2: 48 males received dabigatran (220 mg bid) followed by idarucizumab (n=9/dose group) 1, 2, 4 or 5 g (2×2.5 g), or placebo (n=3/dose group). Anti‐idarucizumab antibodies (ADAs) and idarucizumab effect on anticoagulation parameters (diluted thrombin time [dTT], ecarin clotting time [ECT], activated partial thromboplastin time [aPTT] and thrombin time [TT]) were assessed.ResultsNo adverse events were reported in subjects receiving idarucizumab. After single doses of idarucizumab (alone or at steady state of dabigatran), maximum plasma concentration was achieved around the end of each infusion. Mean all anticoagulation parameters fell below the upper limit of normal immediately after idarucizumab infusion in all dose groups; the effect was sustained at 4 and 2×2.5 g over the entire measurement period until 72 h. At 1‐ and 2‐g doses, partial return of the anticoagulant effect occurred. Idarucizumab alone had no effect on coagulation parameters. Treatment‐emergent ADAs occurred in 6/60 males receiving idarucizumab.ConclusionsIdarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran‐induced anticoagulation in Japanese volunteers. Idarucizumab was well tolerated with no procoagulant effects. Trial registration number: ClinicalTrials.gov NCT02028780 (completed)

Idarucizumab for Emergency Reversal of Anticoagulant Effects of Dabigatran: Interim Results of a Japanese Post-Marketing Surveillance Study

“…As idarucizumab is specific to dabigatran, it does not promote or inhibit thrombosis [9,10]. Phase I studies in Caucasian and Japanese subjects [9,11,12] and the global phase III study (RE-VERSE AD) [13] showed that idarucizumab rapidly reverses the anticoagulant effect of dabigatran.…”

Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran

“…A decreased immune response in the very elderly may account for this. The age of patients in this study (mean, 76.6 years; median, 78 years) was substantially higher compared with the volunteers in phase I (mean, 36 years; median, 32 years) . Overall, anti‐idarucizumab ADAs were detected in a small fraction (5.6%) of the investigated patient population.…”

Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis

“…Details on all utilized clinical studies and on their assignment to a test or training dataset are provided in Table 1 and Table S1 of the Electronic Supplementary Material (ESM). For the presented PBPK analysis, experimental data of five published clinical trials were available [14,[17][18][19][20][21][22][23], including healthy, elderly, and renally impaired Caucasian individuals, healthy Japanese individuals, and a diverse group of patients requiring dabigatran reversal. Idarucizumab was applied intravenously in doses between 20 mg and 8000 mg, either alone or in combination with orally applied, steady-state dabigatran (150 mg or 220 mg of dabigatran etexilate).…”

“…S8 and S9 of the ESM, illustrating the good prediction of the drastic reduction of dabigatran plasma concentrations by idarucizumab. [14,17]; e, f Caucasian individuals with mild renal impairment (RI), pre-treated with 150 mg of DE bid [14,17], and g, h healthy Japanese individuals [19,21].…”

“…Furthermore, the administration of 1 × 2500 mg idarucizumab as a 2-h infusion markedly reduces the rebound effect compared with the administration of 1 × 2500 mg as a bolus injection. Coagulation times as functions of unbound sum dabigatran (unb sum DAB) plasma concentrations (left column), in representative effect-time plots (middle) during dabigatran etexilate (DE) treatment (220 mg twice a day (bid), for 3.5 days) followed by administration of 1000 mg of idarucizumab (IDA) for dabigatran reversal (at 242 h, arrow) in healthy Japanese individuals [19,21] and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model performance in goodness-of-fit plots (right column). Clinically observed data are shown as dots; colored solid lines indicate the model predicted coagulation times.…”