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Coagulation and Fibrinolysis
A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran Stephan Glund1*; Viktoria Moschetti2*; Stephen Norris3; Joachim Stangier1; Michael Schmohl1; Joanne van Ryn1; Benjamin Lang1; Steven Ramael4; Paul Reilly3 1Boehringer
Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany; 2Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 3Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA; 4SGS Life Science Services, Clinical Pharmacology Unit, Antwerp, Belgium
Summary Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18–45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concenCorrespondence to: Dr. Stephan Glund Boehringer Ingelheim Pharma GmbH & Co KG Biberach an der Riß, Germany Tel.: +49 7351 54 93817, Fax: +49 7351 54 90170 E-mail: [email protected]
* These authors contributed equally. Clinical trial registration: http://clinicaltrials.gov/ct2/show/ NCT01688830?term=NCT01688830&rank=1 (NCT01688830).
Introduction Dabigatran etexilate, an oral direct thrombin inhibitor, is registered worldwide for the prevention of stroke in atrial fibrillation, and for the treatment and prevention of venous thromboembolism (1–5). The overall bleeding profile (1–4) and the outcome of major bleeding (6) are favourable for dabigatran compared with warfarin. However, as for all anticoagulants, bleeding remains a relevant side effect. Management of bleeding in dabigatran-treated patients is similar to that of warfarin-induced bleeding; it consists primarily of supportive care targeted for haemodynamic stabilisation and, in rare cases, treatment with coagulation factor concentrates or haemodialysis (6–9). A specific fast-acting antidote could provide a further treatment option for use in emergency situations. Idarucizumab (molecular weight 47.8 kDaltons, previously referred to as aDabi-Fab, BI 655075) is a humanised mouse mono© Schattauer 2015
trations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.
Keywords Antidote, dabigatran etexilate, idarucizumab, reversal agent, safety
Financial support: This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. Received: December 23, 2014 Accepted after major revision: February 20, 2015 Epub ahead of print: March 19, 2015 http://dx.doi.org/10.1160/TH14-12-1080 Thromb Haemost 2015; 113: 943–951
clonal antibody fragment (Fab) that specifically binds and neutralises dabigatran in experimental models, with a binding affinity in the picomolar range, ~350-fold greater than that of dabigatran for thrombin (10). In in vitro studies, idarucizumab showed no binding to known thrombin substrates, and no activity in coagulation or platelet aggregation tests (10, 11). In rats, idarucizumab administered as an intravenous bolus injection rapidly reversed the anticoagulant activity of dabigatran (10). Idarucizumab was also associated with reduction in trauma-induced bleeding in a porcine model of dabigatran anticoagulation (12). In this first-in-human study, we assessed the pharmacokinetics, safety and tolerability of ascending doses of idarucizumab administered intravenously as a long infusion or a bolus, and the effect of idarucizumab on coagulation parameters.
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Materials and methods
Assessments
This phase I study (NCT01688830) was conducted between September 2012 and November 2013 at SGS Life Science Services, Clinical Pharmacology Unit, Antwerp, Belgium.
Idarucizumab pharmacokinetic parameters
Study subjects and conduct Healthy male volunteers aged 18–45 years with a body mass index of 18.5–29.9 kg/m2 were included. Exclusion criteria included any illness or infection, or abnormal values for prothrombin time, activated partial thromboplastin time (aPTT) and platelet count that were considered by the investigator to be clinically relevant. The study protocol was approved by the independent ethics committee. The trial was carried out in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonisation good clinical practice, and in accordance with applicable regulatory requirements. All subjects provided written informed consent.
Study design This was a randomised, double-blind placebo-controlled (within dose groups) study consisting of three parts. Part 1, reported here, comprised a single ascending-dose study in which each of 10 groups received a different dose of idarucizumab (from 20 mg to 8 g) as an intravenous infusion over 1 hour (h), and a further three groups received a dose of 1, 2 or 4 g idarucizumab as a five-minute intravenous infusion. In parts 2 and 3, reversal of the anticoagulant effects of dabigatran by different doses of idarucizumab was evaluated in subjects with steady-state plasma levels of dabigatran (Glund et al., submitted for publication). The randomisation list was generated using a pseudo-random number generator and a supplied seed number. In Part 1, within each dose group eight subjects were randomised in a 3:1 ratio to a single dose of idarucizumab or to matching placebo infusion. The randomisation list was provided to an unblinded pharmacist at the trial site in advance. Participants and care providers were kept blinded to treatment. To ensure safety, each dose group was further divided into three subgroups: A and B (n=2), and C (n=4); there was a 30-minute (min) or 1-h interval between administration of idarucizumab to each subject in subgroups A and B, and a 21-h safety period before administration to subgroups B and C. Subsequent ascending doses were administered in a consecutive fashion, with at least a 72-h interval between dose groups (after last administration of study drug at the previous dose level) for evaluation of safety data. Each subject remained at the clinic for at least 48 h after administration of study drug to cover the expected period of idarucizumab elimination. Idarucizumab (50 mg/ml) and matching placebo were provided by the department of pharmaceutical development at Boehringer Ingelheim Pharma GmbH & Co. KG (Biberach an der Riß, Germany).
Blood samples for pharmacokinetic analysis were collected at 21 time points up to 72 h post-treatment administration. Urine samples were taken cumulatively during defined sampling intervals. Idarucizumab pharmacokinetic parameters Cmax (maximum measured concentration in plasma), tmax (time from dosing to maximum measured concentration), AUC0–∞ (area under the concentration–time curve in plasma, from time zero extrapolated to infinity) and the amount of analyte eliminated in urine between defined time points were assessed. Blood samples were collected into K3-EDTA anticoagulant blood drawing vials, and plasma was prepared by centrifuging at 2,000 to 4,000 g at 4 °C to 8 °C for ~10 min. Idarucizumab concentrations in plasma and urine were measured by a validated enzyme-linked immunosorbent assay (ELISA) method at Covance Laboratories, Inc (Chantilly, VA, USA). The microtitre plate was coated with anti-idarucizumab antibody (anti-id 5H4). After an overnight incubation, the plates were blocked, washed and incubated with diluted calibrators, quality controls and samples previously spiked with a saturating concentration of dabigatran. It had been found that the affinity of anti-id 5H4 for idarucizumab was increased in the presence of dabigatran; therefore, a saturating concentration of dabigatran was added to ensure a constant affinity of this trapping antibody for idarucizumab across samples. Bound analyte detection was performed with anti-human immunoglobulin G horseradish peroxidase. Tetramethyl benzidine substrate was then used to read colourimetrically on a plate reader. The results were analysed with a five-parameter logistic fit in SoftMax Pro software version 5.0.1 or higher (Molecular Devices LLC, Sunnyvale, CA, USA).
Pharmacodynamic parameters Blood samples for analysis of diluted thrombin time (dTT), ecarin clotting time (ECT), thrombin time (TT) and aPTT were collected from the 8 g (1-h) and 4 g (5-min) infusion groups prior to the infusion of idarucizumab and 15 min after the end of the infusion. At the same time points, samples for analysis of endogenous thrombin generation potential (ETP) were obtained and activated clotting time (ACT) was determined. dTT, ECT, TT and aPTT were analysed from citrated plasma samples (0.109 M sodium citrate) collected by venipuncture using validated assays (13, 14). For all coagulation assays, dabigatran calibration and quality control samples were included in order to monitor assay performance over time. Kaolin ACT was determined from fresh whole blood using an Abbott i-STAT point of care device (Abbott Point of Care Inc., Princeton, NJ, USA) according to the manufacturer’s instructions. Coefficient of variation was calculated to describe the inter-individual variability associated with each assay at each time point. ETP, i. e. the area under the thrombin concentration–time curve (AUC), was measured in citrated (0.109 M sodium citrate)
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Glund, Moschetti et al. Safety, tolerability and pharmacokinetics of idarucizumab
platelet-poor plasma by calibrated automated thrombography (CAT; Thrombinoscope BV, Maastricht, The Netherlands) according to the manufacturer’s instructions. Sample analysis was carried out at the Department of Drug Metabolism and Pharmacokinetics at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Blood samples for measurement of human anti-idarucizumab antibodies were taken at baseline, at the end of study visit (6–14 days post-infusion), and at 4 weeks and 3 months post-treatment administration. Human anti-idarucizumab antibodies (ADA) were detected in plasma samples using a validated drug-bridging electrochemiluminescent method. The method employed a tiered approach with the following components: a) a screening assay to identify putative positive samples, b) a confirmatory assay using idarucizumab to confirm a sample as positive, and c) a titration assay. In addition, the specificity of ADA was further assessed using tool antibodies: Mab1, the entire monoclonal antibody that includes the idarucizumab Fab portion; and Fab1, an antibody fragment with constant regions identical to idarucizumab but with different variable regions. Blocking of a response only by Mab1 suggests the presence of ADA that bind to the variable regions, whereas blocking by both Mab1 and Fab1 suggests the presence of ADA that bind to the constant regions. Blocking of a response only by Fab1 suggests the presence of ADA that bind to an epitope at or near the C-terminus of idarucizumab, an epitope that is present in all Fabs after cleavage from a monoclonal antibody and not specific for the dabigatran binding site on idarucizumab.
Safety The primary study end point was the number (%) of subjects with adverse events (AEs) arising during the treatment period that were considered by the investigator to be drug-related. The treatment period for analysis of AEs, defined as the time from treatment administration until the end-of-study visit, spanned 6–14 days (including a time window of 9 days for the end-ofstudy visit). AEs occurring after this visit were assigned to the
follow-up period, extending to approximately three months after administration of idarucizumab. Physical examination, assessment of vital signs, 12-lead electrocardiogram (ECG), continuous ECG and pO2 monitoring, clinical laboratory tests and assessment of local tolerability were also performed. An increase in body temperature above 38 °C, a drop in peripheral capillary oxygen saturation below 90 %, a drop in systolic blood pressure below 90 mm Hg, an increase in resting heart rate above 100 beats/min and any symptoms of respiratory distress were defined as significant (pre-specified) AEs. Any AEs occurring after trial completion were monitored for three months, or until they had either normalised or been sufficiently characterised.
Analysis methods All analyses were descriptive. All randomised subjects who received at least one dose of trial medication were included in the safety evaluation. Pharmacokinetic and pharmacodynamic evaluations included treated subjects who had no relevant protocol violations and at least one evaluable pre-dose and/or on-treatment observation.
Results Subjects In total, 110 subjects were randomised (86 to the 1-h infusion groups and 24 to the 5-min infusion groups), received study treatment and were included in the safety analysis. All enrolled subjects completed the trial. Each dose group analysed comprised two subjects on placebo and six on idarucizumab, except for the 600 mg 1-h infusion group (five idarucizumab subjects), the 4 g 1-h infusion group (one placebo subject) and the 2 g 1-h infusion group (12 idarucizumab and four placebo subjects). The extra subjects in the 2 g 1-h group resulted from incorrect dosing, with two groups of volunteers receiving 2 g idarucizumab or placebo. Demographic characteristics were generally similar for the different treatment
Table 1: Demographic and baseline characteristics of subjects receiving the 5-min or 1-h infusion of idarucizumab (13 dose groups).a
Idarucizumab (1 h)
Idarucizumab (5 min)
Pbo 1h
20 mg
60 mg
200 mg
600 mg
1.2 g
2g
3g
4g
6g
8g
Pbo 1g 5 min
2g
4g
21
6
6
6
5
6
12
6
6
6
6
6
6
6
6
Age, mean ± SD, years 30.3 ±7.8
29.8 ± 6.6
35.2 ± 5.5
36.2 ± 8.8
36.6 ± 4.5
32.0 ± 8.9
30.3 ± 8.5
32.7 ± 4.2
35.3 ± 9.5
34.5 ± 8.8
35.2 ± 9.1
34.5 ±11.2
34.7 ± 8.5
31.8 ± 5.4
36.0 ± 8.3
Weight, mean ± SD, kg 72.1 ±5.5
79.5 79.8 80.8 ± 15.1 ± 11.8 ± 2.9
90.2 ± 8.7
82.7 ± 8.8
81.3 ± 9.3
83.0 71.8 ± 10.4 ± 9.5
83.2 ± 9.8
80.8 ± 4.8
77.3 ±2.7
72.8 ± 3.5
72.7 82.2 ± 12.4 ± 14.3
Body mass index, mean ± SD, kg/m2
24.5 ± 3.0
27.1 ± 2.4
25.3 ± 3.2
24.1 ± 2.3
26.0 ± 2.6
25.2 ± 2.9
24.6 ± 2.0
23.8 ±2.4
23.6 ± 1.6
23.5 ± 3.5
Subjects, N
22.6 ±2.0
24.0 ± 1.9
25.8 ± 1.6
22.8 ± 2.5
24.1 ± 2.8
aAll
subjects were white, except for the following: one Asian, placebo 1-h infusion group; one black/African American, idarucizumab 2 g 1-h infusion group; one American Indian/Alaska native, idarucizumab 2 g 5-min infusion group. Pbo, placebo; SD, standard deviation.
© Schattauer 2015
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groups (▶ Table 1). All 83 subjects who received idarucizumab were included in the pharmacokinetic analysis, and all 16 subjects in the 8 g 1-h and 4 g 5-min dose groups were included in the pharmacodynamic analysis.
Over the first urine collection interval (0–4 h from treatment administration), 2.23, 8.00 and 32.6 µmol of idarucizumab (geometric mean data) were detected in urine for the five-minute 1 g, 2 g and 4 g infusions of idarucizumab, respectively; this corresponds to 10.7 %, 19.1 % and 38.9 % of the administered dose, indicating a dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine. Over subsequent urine collection intervals, idarucizumab was either undetectable in urine, or present in negligible amounts. At the sampling time for blood coagulation parameters, the idarucizumab plasma concentrations were 27,700 and 18,800 nmol/l for the idarucizumab 4 g (5-min) and 8 g (1-h) infusion groups, respectively.
Idarucizumab pharmacokinetics Pharmacokinetic parameters for idarucizumab for all 5-min and 1-h infusion dose groups are shown in ▶ Table 2. Peak concentrations were achieved at or shortly after the end of the 1-h or 5-min infusions. Geometric mean peak exposure (Cmax) and total exposure (AUC0–∞) both increased proportionally with dose (▶ Table 2). Peak concentrations were followed by a rapid mono- to biphasic decline in plasma concentrations (▶ Figure 1 and ▶ Figure 2). The geometric mean initial half-life was short, ranging from 39–54 min across doses. At 4 h after the end of the 5-min infusions, geometric mean idarucizumab plasma concentrations had decreased to approximately 4 % or less of peak concentrations. The terminal half-life for idarucizumab doses ≥ 600 mg ranged from geometric mean 4.5–8.1 h. Trace amounts of idarucizumab were detectable in plasma for up to 16 h after infusion of 1 g and up to 24 h after infusion of higher doses. The distribution volume of idarucizumab at steady state approximated the blood volume; the volume of distribution during the terminal phase ranged from 17.6–37.9 liters for idarucizumab doses of ≥ 600 mg.
Pharmacodynamics Baseline values for all coagulation parameters are shown in ▶Table 3. At doses of 8 g infused over 1 h and 4 g infused over 5 min, idarucizumab had no effect on the coagulation markers determined 15 min after the end of the infusion when idarucizumab plasma levels were highest (▶ Table 3). Inter-individual variability of pharmacodynamic response was low for all coagulation parameters, with coefficient of variation values ranging from 0.87–16.9 % for both time points. The lowest variability was achieved with the dTT assay (coefficient of variation range 0.87–1.80 %), followed by the TT, ECT and aPTT; the ACT showed the highest variability between individuals (▶ Table 3).
Table 2: Pharmacokinetic parameters of idarucizumab following 1-h or 5-min infusion (13 dose groups).
Idarucizumab (1 h)
Idarucizumab (5 min)
20 mg 60 mg 200 mg 600 mg 1.2 g
2g
3g
4g
6g
8g
1g
2g
4g
Subjects, N
6
6
6
5
6
12
6
6
6
5
6
6
6
AUC0–∞, nmol·h/l, gMean (gCV, %)
146 (19.8)
426 (11.6)
1950 (129)
6970 (75.4)
8780 (4.92)
14500 (15.9)
22600 (17.6)
31000 (12.9)
41200 (11.8)
63800 (15.6)
7790 (13.1)
16400 (16.8)
25800 (22.1)
AUC0–∞, norm nmol·h/l/mg, gMean (gCV, %)
7.29 (19.8)
7.11 (11.6)
9.77 (129)
11.6 (75.4)
7.32 (4.92)
7.27 (15.9)
7.53 (17.6)
7.76 (12.9)
6.87 (11.8)
7.97 (15.6)
7.79 (13.1)
8.19 (16.8)
6.46 (22.1)
Cmax, nmol/l, gMean (gCV, %)
79.9 (15.1)
257 (11.1)
809 (13.9)
2440 (13.1)
4520 (9.72)
7420 (15.1)
11700 (10.4)
15700 (15.6)
22100 (12.0)
33900 (13.2)
6360 (16.7)
13600 (23.4)
21400 (13.1)
Cmax,norm nmol/l/mg, gMean (gCV, %)
3.99 (15.1)
4.29 (11.1)
4.05 (13.9)
4.07 (13.1)
3.77 (9.72)
3.71 (15.1)
3.92 (10.4)
3.91 (15.6)
3.68 (12.0)
4.24 (13.2)
6.36 (16.7)
6.78 (23.4)
5.34 (13.1)
tmax, h median (min–max)
1.00 1.03 1.03 (0.967– (0.967– (0.967– 1.17) 1.17) 1.08)
1.10 (1.03– 1.18)
0.967 (0.967– 1.08)
0.984 1.00 1.06 1.03 1.08 0.117 0.142 (0.967– (0.967– (0.967– (0.967– (0.967– (0.0830– (0.117– 1.17) 1.05) 1.17) 1.08) 1.17) 0.167) 0.250)
0.167 (0.117– 0.250)
t1/2, h, gMean (gCV, %)
0.887 (18.1)
0.978 (12.6)
2.13 (329)
7.9 (213)
5.52 (24.1)
6.96 (31.9)
7.62 (12.0)
7.65 (12.2)
6.83 (9.80)
6.73 (4.77)
4.54 (17.9)
7.42 (33.1)
8.11 (11.1)
t1/2, 2, h, gMean (gCV, %)
0.777 (27.3)
0.746 (18.8)
0.658 (23.0)
0.725 (10.4)
0.906 (12.6)
0.782 (12.6)
0.779 (7.14)
0.796 (15.6)
0.888 (6.31)
0.850 (13.2)
0.751 (22.2)
0.773 (5.39)
0.725 (17.6)
AUC, area under curve; Cmax, maximum measured concentration in plasma; gCV, geometric coefficient of variation; gMean, geometric mean; tmax, time from dosing to maximum measured concentration; t1/2, terminal half-life; t1/2, 2, initial half-life.
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Figure 1: Geometric mean idarucizumab plasma concentration–time profiles from the start of a single infusion of 20 mg to 8 g idarucizumab for 1 h on a linear scale (A) and a semi-log scale (B).
Infusions of idarucizumab at these doses also had no effect on the ETP at the time point measured, indicating the absence of prothrombotic properties of idarucizumab (▶ Figure 3).
Safety No clinically relevant differences in the overall incidence of AEs in subjects receiving placebo or idarucizumab were observed. In total, 42 of 110 subjects (38.2 %) reported at least one AE during the treatment period (12 of 27 subjects on placebo, and 30 of 83 subjects on idarucizumab [Suppl. Table 1, available online at www. thrombosis-online.com]). The most frequently reported AEs were headache, nasopharyngitis, back pain and skin irritation (▶Table 4). There were no serious AEs, protocol-specified significant AEs, other significant AEs or AEs leading to discontinuation of trial drug during the treatment period. The majority of AEs were of mild intensity. No relationship between dose and frequency of AEs was observed. AEs assessed as drug-related by the investigator occurred in five of 110 (4.5 %) subjects (two placebo subjects and three idarucizumab subjects) during the treatment period. Of the two subjects on placebo (1-h infusion), one reported pain in extremity, and one had upper abdominal pain and chest pain. Two subjects in © Schattauer 2015
the 2-g idarucizumab (1-h) dose group reported headache (both subjects) and erythema at the infusion site (one subject), and one subject in the 8-g idarucizumab (1-h) dose group had migraine. All drug-related AEs were of mild intensity, except for the migraine; the migraine was of moderate intensity and was probably caused by the study procedure. No AEs that were considered drugrelated were reported during the follow-up period. There were no clinically relevant findings in laboratory parameters, vital signs, electrocardiogram, cardiac telemetry and physical examination. A dose-dependent, transient increase in urine protein and low-weight proteins was observed in subjects who received idarucizumab. However, there were no corresponding changes indicating acute tubular injury or loss of function, and values returned to normal range within 4–12 h after end of infusion. There were no local tolerability reactions in subjects receiving five-minute infusions of idarucizumab 1–4 g. Among subjects in the 1-h dose groups, one subject receiving 8 g idarucizumab reported swelling at the infusion site, one subject receiving 2 g idarucizumab had redness and pain at the infusion site, and another subject on placebo reported pain at the infusion site. All skin reactions were of mild intensity. No clinically relevant local skin reactions were observed in the two subjects (200 mg, 1-h infusion; and Thrombosis and Haemostasis 113.5/2015
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Figure 2: Geometric mean idarucizumab plasma concentration–time profiles from the start of a single infusion of 1 g to 4 g idarucizumab for 5 min on a linear scale (A) and a semi-log scale (B).
8 g, 1-h infusion) in whom idarucizumab was infused partly paravenously. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in 13 of 110 subjects (four of 27 subjects randomised to placebo and nine of 83 subjects randomised to idarucizumab). Most subjects with anti-idarucizumab antibodies at pre-dose
tested positive throughout the study. These antibodies were directed to the C-terminus of the Fab and not to the dabigatranbinding portion of the Fab. Three subjects with idarucizumab and one subject with placebo had a transient, low titre antibody response, which was not observed at subsequent time points. There were no AEs consistent with immunogenic reactions.
8 g idarucizumab, 1-h infusion
4 g idarucizumab, 5-min infusion
Baseline (N=6)
Baseline (N=6)
15 min postinfusion (N=5)
15 min postinfusion (N=6)
Mean ± SD, s
CV, % Mean ± SD, s
CV, % Mean ± SD, s
CV, %
Mean ± SD, s
CV, %
dTT
32.0 ± 0.3
0.871
31.5 ± 0.4
1.16
31.9 ± 0.3
0.986
31.4 ± 0.6
1.80
ECT
37.3 ± 3.8
10.2
39.2 ± 5.3
13.4
36.6 ± 1.3
3.58
37.8 ± 1.9
4.93
TT
11.9 ± 0.5
4.29
12.3 ± 0.8
6.42
11.7 ± 1.0
8.36
11.7 ± 1.0
8.46
aPTT
31.4 ± 4.9
15.5
33.4 ± 4.8
14.3
32.8 ± 3.1
9.37
31.9 ± 2.4
7.60
ACT
114 ± 19.3
16.9
110 ± 13.5
12.3
112 ± 9.0
8.00
104 ± 12.8
12.4
Table 3: Blood coagulation times determined as dTT, ECT, TT, aPTT and ACT, before and after infusion of idarucizumab.
ACT, activated clotting time; aPTT, activated partial thromboplastin time; CV, coefficient of variation; dTT, diluted thrombin time; ECT, ecarin clotting time; s, seconds; SD, standard deviation; TT, thrombin time.
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8 g, 1-h Infusion
4 g, 5-min Infusion
Figure 3: Effect of idarucizumab administered as an 8 g infusion over 1 h and a 4 g infusion over 5 min on endogenous thrombin generation potential (mean thrombin area under concentration curve [AUC]). Values were determined at baseline and 15 minutes after the end of the infusion. Error bars show standard deviation from the mean.
Discussion In this first-in-human study, idarucizumab was safe and well tolerated when administered to healthy male subjects in single rising doses from 20 mg to 8 g over 1 h or from 1–4 g over 5 min. Peak plasma concentrations of idarucizumab were achieved at the end of infusion, which would ensure immediate availability in plasma for dabigatran binding. Idarucizumab concentrations then rapidly declined to 4 % or less of peak concentrations after 4 h, with an initial half-life of ~45 min. The low volume of distribution and the observed renal excretion over the first 4-h collection interval suggest that this initial decline was dominated by renal elimination processes. As with most small proteins, a major fraction of
idarucizumab is expected to be eliminated by renal catabolism (15). The dose-dependent increase in the fraction of unchanged drug excreted into urine suggest saturation of renal tubule receptors responsible for reuptake of filtered proteins (16); these findings are consistent with studies assessing the renal reuptake of other Fabs (17, 18). In in vitro studies, equimolar concentrations of idarucizumab, i. e. 1:1 stoichiometry of dabigatran and idarucizumab, were required for complete neutralisation of the dabigatran anticoagulant effect (10). We calculated based on median peak concentrations of dabigatran seen in atrial fibrillation patients from the RE-LY study who received 150 mg dabigatran twice daily (1) that an equimolar ratio of idarucizumab to the total body load of
Table 4: Frequency of subjects with adverse events, and adverse events occurring in ≥ 2 subjects, across all dose groups of idarucizumab.
n (%)
Placebo Idarucizumab (1 h and 5 min) 20 mga 60 mga
200 mga 600 mga 1–1.2 gb 2 gc
3 ga
4 gd
6 ga
8 ga
Total
Subjects, N
27
6
6
6
5
12
18
6
12
6
6
83
Subjects with AEs
12 (44.4)
2 (33.3)
2 (33.3)
5 (83.3)
2 (40.0)
4 (33.3)
6 (33.3) 3 (50.0) 3 (25.0) 1 (16.7) 2 (33.3) 30 (36.1)
Headache
2 (7.4)
1 (16.7)
0
2 (33.3)
0
1 (8.3)
2 (11.1) 1 (16.7) 2 (16.7) 0
0
Nasopharyngitis
2 (7.4)
0
1 (16.7)
0
1 (20.0)
0
1 (5.6)
0
0
0
1 (16.7) 4 (4.8)
Back pain
1 (3.7)
0
0
0
1 (20.0)
2 (16.7)
0
1 (16.7) 0
0
0
4 (4.8)
Skin irritation
2 (7.4)
0
0
1 (16.7)
0
0
0
1 (16.7) 0
1 (16.7) 0
3 (3.6)
Catheter site pain
1 (3.7)
0
0
1 (16.7)
0
0
1 (5.6)
0
0
0
0
2 (2.4)
Pain in extremity 1 (3.7)
0
1 (16.7)
0
0
0
1 (5.6)
0
0
0
0
2 (2.4)
Diarrhoea
0
1 (16.7)
0
0
0
0
0
1 (16.7) 0
0
0
2 (2.4)
Dizziness
1 (3.7)
1 (16.7)
0
0
0
0
0
0
0
0
0
1 (1.2)
Migraine
0
0
0
0
0
1 (8.3)
0
0
0
0
1 (16.7) 2 (2.4)
Musculoskeletal stiffness
0
0
0
1 (16.7)
0
0
0
0
0
0
1 (16.7) 2 (2.4)
9 (10.8)
a1-h
infusion. bData pooled from the 1.2 g 1-h infusion group and the 1 g 5-min infusion group. cData pooled from the 2 g 1-h infusion group and the 2 g 5-min infusion group. dData pooled from the 4 g 1-h infusion group and the 4 g 5-min infusion group. Data from treatment period. AE, adverse event.
© Schattauer 2015
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dabigatran would be provided by a 2-g dose of idarucizumab. However, trough plasma concentrations varied more than five-fold in RE-LY (19), and higher concentrations than the median may require higher doses of idarucizumab for full reversal. Patients with bleeding may also have elevated concentrations compared with patients without major bleeding (19). In the present study, the highest doses of idarucizumab used (4 g over 5 min, and 8 g over 1 h) therefore correspond to 200 % and 400 % of the predicted dose of idarucizumab that will completely neutralise the median peak dabigatran concentrations observed in patients. Thus the expected clinical dose of 5 g is judged to be both effective and safe. Administration of idarucizumab at doses up to 8 g did not appear to result in any elevated procoagulant or anti-coagulant activity in the plasma of these healthy subjects. No effect on blood coagulation as assessed by dTT, ECT, aPTT or TT, or the bedside test ACT, at 15 min after the end of the infusion could be observed. In addition, idarucizumab did not affect the ETP. These findings are consistent with in vitro data showing no effect of idarucizumab alone (at concentrations up to 3 mg/ml) on clotting in a dTT assay and no effect on ETP (10). Also consistent with our findings, binding studies indicated that idarucizumab does not bind to known endogenous thrombin targets, despite some structural similarities to thrombin and its high affinity for dabigatran (10). The AE profile of idarucizumab revealed no unexpected or clinically relevant safety concerns, with the observed AEs mostly of mild intensity, and no relationship between idarucizumab dose and AE frequency. In addition, no clinically relevant changes in any of the safety parameters were observed. No formation of persistent new antibodies against idarucizumab was detected in these 110 subjects; however, data from a larger number of subjects are required to allow a conclusive evaluation of immunogenicity. A
What is known about this topic?
• • •
All anticoagulants carry an inherent risk of bleeding, which can be fatal in rare cases. No specific reversal agents are currently available for any of the oral anticoagulants. Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity, and is in development as a specific antidote for dabigatran.
What does this paper add?
•
•
Idarucizumab was safe and well tolerated after intravenous infusion in healthy volunteers. Its pharmacological profile met the requirement for rapid peak exposure followed by rapid elimination, with no effect on pharmacodynamic parameters when administered alone. These first-in-human data support the continued development of idarucizumab as a reversal agent for dabigatran. Idarucizumab could provide a further treatment option for use in emergency bleeding situations, if safety and efficacy in reversing dabigatraninduced anticoagulation are confirmed in further studies.
dose-dependent, transient increase in urine protein and lowweight proteins, concurrent with the transient urinary excretion of idarucizumab, may indicate saturation of tubular uptake processes for the reabsorption of proteins from the filtrate (16). While this study demonstrates the safety of idarucizumab in doses exceeding the planned clinical dose of 5 g and suggests that idarucizumab has the potential for use in patients as a rapid reversal agent for dabigatran, the study has potential limitations. The dose being tested was known to both subjects and investigators, although double-blind conditions around treatment were maintained. The objective nature of the assay results and measured plasma levels limit the potential for observer bias. However, these tests were carried out in healthy volunteers and extrapolation to a patient population with multiple morbidities is required to further assess the safety profile.
Conclusions In this first-in-human study of the specific dabigatran antidote idarucizumab, peak plasma exposure was reached quickly, followed by rapid elimination. In the absence of dabigatran, idarucizumab had no effect on coagulation parameters or ETP. Idarucizumab was safe and well tolerated at all administered doses, as either a 1-h or 5-min infusion. Acknowledgements
The study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. All authors have had full access to data and contributed to drafting the paper. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors and received no compensation related to the development of the manuscript. Medical writing assistance, supported financially by Boehringer Ingelheim Pharma GmbH & Co. KG, was provided by Mary Berrington, PhD, of PAREXEL during the preparation of this article. Conflicts of interest
S. Glund, J. Stangier, M. Schmohl, B. Lang, V. Moschetti, and J. Van Ryn are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. P. Reilly and S. Norris are employees of Boehringer Ingelheim Pharmaceuticals, Inc. S. Ramael was principal investigator of this trial and an employee of SGS Life Science Services, the contract research organisation that was funded by Boehringer Ingelheim Pharma GmbH & Co. KG to perform the clinical trial.
References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151. 2. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342–2352.
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© Schattauer 2015
Glund, Moschetti et al. Safety, tolerability and pharmacokinetics of idarucizumab 3. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764–772. 4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875–1876. 5. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010; 126: 175–182. 6. Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325–2332. 7. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–2106. 8. Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012; 87 (Suppl 1): S119-S126. 9. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–1127. 10. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554–3562. 11. van Ryn J, Litzenburger T, Schurer J. Reversal of anticoagulant activity of dabigatran and dabigatran-induced bleeding in rats by a specific antidote (antibody fragment). Circulation 2012; 126: A9928.
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12. Grottke O, Honickel M, van Ryn J, et al. A specific antidote to dabigatran reduces blood loss in dabigatran- and trauma-induced bleeding in pigs. J Am Coll Cardiol 2014; 63 (12_S). 13. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285–295. 14. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138–143. 15. Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol 2012; 52: 54S-62S. 16. Christensen EI, Birn H, Storm T, et al. Endocytic receptors in the renal proximal tubule. Physiology 2012; 27: 223–236. 17. Behr TM, Sharkey RM, Juweid ME, et al. Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives. Cancer Res 1995; 55: 3825–3834. 18. Behr TM, Becker WS, Sharkey RM, et al. Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion. J Nucl Med 1996; 37: 829–833. 19. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63: 321–328.
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Coagulation and Fibrinolysis
A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran Stephan Glund1*; Viktoria Moschetti2*; Stephen Norris3; Joachim Stangier1; Michael Schmohl1; Joanne van Ryn1; Benjamin Lang1; Steven Ramael4; Paul Reilly3 1Boehringer
Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany; 2Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 3Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA; 4SGS Life Science Services, Clinical Pharmacology Unit, Antwerp, Belgium
Summary Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18–45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concenCorrespondence to: Dr. Stephan Glund Boehringer Ingelheim Pharma GmbH & Co KG Biberach an der Riß, Germany Tel.: +49 7351 54 93817, Fax: +49 7351 54 90170 E-mail: [email protected]
* These authors contributed equally. Clinical trial registration: http://clinicaltrials.gov/ct2/show/ NCT01688830?term=NCT01688830&rank=1 (NCT01688830).
Introduction Dabigatran etexilate, an oral direct thrombin inhibitor, is registered worldwide for the prevention of stroke in atrial fibrillation, and for the treatment and prevention of venous thromboembolism (1–5). The overall bleeding profile (1–4) and the outcome of major bleeding (6) are favourable for dabigatran compared with warfarin. However, as for all anticoagulants, bleeding remains a relevant side effect. Management of bleeding in dabigatran-treated patients is similar to that of warfarin-induced bleeding; it consists primarily of supportive care targeted for haemodynamic stabilisation and, in rare cases, treatment with coagulation factor concentrates or haemodialysis (6–9). A specific fast-acting antidote could provide a further treatment option for use in emergency situations. Idarucizumab (molecular weight 47.8 kDaltons, previously referred to as aDabi-Fab, BI 655075) is a humanised mouse mono© Schattauer 2015
trations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.
Keywords Antidote, dabigatran etexilate, idarucizumab, reversal agent, safety
Financial support: This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. Received: December 23, 2014 Accepted after major revision: February 20, 2015 Epub ahead of print: March 19, 2015 http://dx.doi.org/10.1160/TH14-12-1080 Thromb Haemost 2015; 113: 943–951
clonal antibody fragment (Fab) that specifically binds and neutralises dabigatran in experimental models, with a binding affinity in the picomolar range, ~350-fold greater than that of dabigatran for thrombin (10). In in vitro studies, idarucizumab showed no binding to known thrombin substrates, and no activity in coagulation or platelet aggregation tests (10, 11). In rats, idarucizumab administered as an intravenous bolus injection rapidly reversed the anticoagulant activity of dabigatran (10). Idarucizumab was also associated with reduction in trauma-induced bleeding in a porcine model of dabigatran anticoagulation (12). In this first-in-human study, we assessed the pharmacokinetics, safety and tolerability of ascending doses of idarucizumab administered intravenously as a long infusion or a bolus, and the effect of idarucizumab on coagulation parameters.
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Materials and methods
Assessments
This phase I study (NCT01688830) was conducted between September 2012 and November 2013 at SGS Life Science Services, Clinical Pharmacology Unit, Antwerp, Belgium.
Idarucizumab pharmacokinetic parameters
Study subjects and conduct Healthy male volunteers aged 18–45 years with a body mass index of 18.5–29.9 kg/m2 were included. Exclusion criteria included any illness or infection, or abnormal values for prothrombin time, activated partial thromboplastin time (aPTT) and platelet count that were considered by the investigator to be clinically relevant. The study protocol was approved by the independent ethics committee. The trial was carried out in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonisation good clinical practice, and in accordance with applicable regulatory requirements. All subjects provided written informed consent.
Study design This was a randomised, double-blind placebo-controlled (within dose groups) study consisting of three parts. Part 1, reported here, comprised a single ascending-dose study in which each of 10 groups received a different dose of idarucizumab (from 20 mg to 8 g) as an intravenous infusion over 1 hour (h), and a further three groups received a dose of 1, 2 or 4 g idarucizumab as a five-minute intravenous infusion. In parts 2 and 3, reversal of the anticoagulant effects of dabigatran by different doses of idarucizumab was evaluated in subjects with steady-state plasma levels of dabigatran (Glund et al., submitted for publication). The randomisation list was generated using a pseudo-random number generator and a supplied seed number. In Part 1, within each dose group eight subjects were randomised in a 3:1 ratio to a single dose of idarucizumab or to matching placebo infusion. The randomisation list was provided to an unblinded pharmacist at the trial site in advance. Participants and care providers were kept blinded to treatment. To ensure safety, each dose group was further divided into three subgroups: A and B (n=2), and C (n=4); there was a 30-minute (min) or 1-h interval between administration of idarucizumab to each subject in subgroups A and B, and a 21-h safety period before administration to subgroups B and C. Subsequent ascending doses were administered in a consecutive fashion, with at least a 72-h interval between dose groups (after last administration of study drug at the previous dose level) for evaluation of safety data. Each subject remained at the clinic for at least 48 h after administration of study drug to cover the expected period of idarucizumab elimination. Idarucizumab (50 mg/ml) and matching placebo were provided by the department of pharmaceutical development at Boehringer Ingelheim Pharma GmbH & Co. KG (Biberach an der Riß, Germany).
Blood samples for pharmacokinetic analysis were collected at 21 time points up to 72 h post-treatment administration. Urine samples were taken cumulatively during defined sampling intervals. Idarucizumab pharmacokinetic parameters Cmax (maximum measured concentration in plasma), tmax (time from dosing to maximum measured concentration), AUC0–∞ (area under the concentration–time curve in plasma, from time zero extrapolated to infinity) and the amount of analyte eliminated in urine between defined time points were assessed. Blood samples were collected into K3-EDTA anticoagulant blood drawing vials, and plasma was prepared by centrifuging at 2,000 to 4,000 g at 4 °C to 8 °C for ~10 min. Idarucizumab concentrations in plasma and urine were measured by a validated enzyme-linked immunosorbent assay (ELISA) method at Covance Laboratories, Inc (Chantilly, VA, USA). The microtitre plate was coated with anti-idarucizumab antibody (anti-id 5H4). After an overnight incubation, the plates were blocked, washed and incubated with diluted calibrators, quality controls and samples previously spiked with a saturating concentration of dabigatran. It had been found that the affinity of anti-id 5H4 for idarucizumab was increased in the presence of dabigatran; therefore, a saturating concentration of dabigatran was added to ensure a constant affinity of this trapping antibody for idarucizumab across samples. Bound analyte detection was performed with anti-human immunoglobulin G horseradish peroxidase. Tetramethyl benzidine substrate was then used to read colourimetrically on a plate reader. The results were analysed with a five-parameter logistic fit in SoftMax Pro software version 5.0.1 or higher (Molecular Devices LLC, Sunnyvale, CA, USA).
Pharmacodynamic parameters Blood samples for analysis of diluted thrombin time (dTT), ecarin clotting time (ECT), thrombin time (TT) and aPTT were collected from the 8 g (1-h) and 4 g (5-min) infusion groups prior to the infusion of idarucizumab and 15 min after the end of the infusion. At the same time points, samples for analysis of endogenous thrombin generation potential (ETP) were obtained and activated clotting time (ACT) was determined. dTT, ECT, TT and aPTT were analysed from citrated plasma samples (0.109 M sodium citrate) collected by venipuncture using validated assays (13, 14). For all coagulation assays, dabigatran calibration and quality control samples were included in order to monitor assay performance over time. Kaolin ACT was determined from fresh whole blood using an Abbott i-STAT point of care device (Abbott Point of Care Inc., Princeton, NJ, USA) according to the manufacturer’s instructions. Coefficient of variation was calculated to describe the inter-individual variability associated with each assay at each time point. ETP, i. e. the area under the thrombin concentration–time curve (AUC), was measured in citrated (0.109 M sodium citrate)
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Glund, Moschetti et al. Safety, tolerability and pharmacokinetics of idarucizumab
platelet-poor plasma by calibrated automated thrombography (CAT; Thrombinoscope BV, Maastricht, The Netherlands) according to the manufacturer’s instructions. Sample analysis was carried out at the Department of Drug Metabolism and Pharmacokinetics at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Blood samples for measurement of human anti-idarucizumab antibodies were taken at baseline, at the end of study visit (6–14 days post-infusion), and at 4 weeks and 3 months post-treatment administration. Human anti-idarucizumab antibodies (ADA) were detected in plasma samples using a validated drug-bridging electrochemiluminescent method. The method employed a tiered approach with the following components: a) a screening assay to identify putative positive samples, b) a confirmatory assay using idarucizumab to confirm a sample as positive, and c) a titration assay. In addition, the specificity of ADA was further assessed using tool antibodies: Mab1, the entire monoclonal antibody that includes the idarucizumab Fab portion; and Fab1, an antibody fragment with constant regions identical to idarucizumab but with different variable regions. Blocking of a response only by Mab1 suggests the presence of ADA that bind to the variable regions, whereas blocking by both Mab1 and Fab1 suggests the presence of ADA that bind to the constant regions. Blocking of a response only by Fab1 suggests the presence of ADA that bind to an epitope at or near the C-terminus of idarucizumab, an epitope that is present in all Fabs after cleavage from a monoclonal antibody and not specific for the dabigatran binding site on idarucizumab.
Safety The primary study end point was the number (%) of subjects with adverse events (AEs) arising during the treatment period that were considered by the investigator to be drug-related. The treatment period for analysis of AEs, defined as the time from treatment administration until the end-of-study visit, spanned 6–14 days (including a time window of 9 days for the end-ofstudy visit). AEs occurring after this visit were assigned to the
follow-up period, extending to approximately three months after administration of idarucizumab. Physical examination, assessment of vital signs, 12-lead electrocardiogram (ECG), continuous ECG and pO2 monitoring, clinical laboratory tests and assessment of local tolerability were also performed. An increase in body temperature above 38 °C, a drop in peripheral capillary oxygen saturation below 90 %, a drop in systolic blood pressure below 90 mm Hg, an increase in resting heart rate above 100 beats/min and any symptoms of respiratory distress were defined as significant (pre-specified) AEs. Any AEs occurring after trial completion were monitored for three months, or until they had either normalised or been sufficiently characterised.
Analysis methods All analyses were descriptive. All randomised subjects who received at least one dose of trial medication were included in the safety evaluation. Pharmacokinetic and pharmacodynamic evaluations included treated subjects who had no relevant protocol violations and at least one evaluable pre-dose and/or on-treatment observation.
Results Subjects In total, 110 subjects were randomised (86 to the 1-h infusion groups and 24 to the 5-min infusion groups), received study treatment and were included in the safety analysis. All enrolled subjects completed the trial. Each dose group analysed comprised two subjects on placebo and six on idarucizumab, except for the 600 mg 1-h infusion group (five idarucizumab subjects), the 4 g 1-h infusion group (one placebo subject) and the 2 g 1-h infusion group (12 idarucizumab and four placebo subjects). The extra subjects in the 2 g 1-h group resulted from incorrect dosing, with two groups of volunteers receiving 2 g idarucizumab or placebo. Demographic characteristics were generally similar for the different treatment
Table 1: Demographic and baseline characteristics of subjects receiving the 5-min or 1-h infusion of idarucizumab (13 dose groups).a
Idarucizumab (1 h)
Idarucizumab (5 min)
Pbo 1h
20 mg
60 mg
200 mg
600 mg
1.2 g
2g
3g
4g
6g
8g
Pbo 1g 5 min
2g
4g
21
6
6
6
5
6
12
6
6
6
6
6
6
6
6
Age, mean ± SD, years 30.3 ±7.8
29.8 ± 6.6
35.2 ± 5.5
36.2 ± 8.8
36.6 ± 4.5
32.0 ± 8.9
30.3 ± 8.5
32.7 ± 4.2
35.3 ± 9.5
34.5 ± 8.8
35.2 ± 9.1
34.5 ±11.2
34.7 ± 8.5
31.8 ± 5.4
36.0 ± 8.3
Weight, mean ± SD, kg 72.1 ±5.5
79.5 79.8 80.8 ± 15.1 ± 11.8 ± 2.9
90.2 ± 8.7
82.7 ± 8.8
81.3 ± 9.3
83.0 71.8 ± 10.4 ± 9.5
83.2 ± 9.8
80.8 ± 4.8
77.3 ±2.7
72.8 ± 3.5
72.7 82.2 ± 12.4 ± 14.3
Body mass index, mean ± SD, kg/m2
24.5 ± 3.0
27.1 ± 2.4
25.3 ± 3.2
24.1 ± 2.3
26.0 ± 2.6
25.2 ± 2.9
24.6 ± 2.0
23.8 ±2.4
23.6 ± 1.6
23.5 ± 3.5
Subjects, N
22.6 ±2.0
24.0 ± 1.9
25.8 ± 1.6
22.8 ± 2.5
24.1 ± 2.8
aAll
subjects were white, except for the following: one Asian, placebo 1-h infusion group; one black/African American, idarucizumab 2 g 1-h infusion group; one American Indian/Alaska native, idarucizumab 2 g 5-min infusion group. Pbo, placebo; SD, standard deviation.
© Schattauer 2015
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groups (▶ Table 1). All 83 subjects who received idarucizumab were included in the pharmacokinetic analysis, and all 16 subjects in the 8 g 1-h and 4 g 5-min dose groups were included in the pharmacodynamic analysis.
Over the first urine collection interval (0–4 h from treatment administration), 2.23, 8.00 and 32.6 µmol of idarucizumab (geometric mean data) were detected in urine for the five-minute 1 g, 2 g and 4 g infusions of idarucizumab, respectively; this corresponds to 10.7 %, 19.1 % and 38.9 % of the administered dose, indicating a dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine. Over subsequent urine collection intervals, idarucizumab was either undetectable in urine, or present in negligible amounts. At the sampling time for blood coagulation parameters, the idarucizumab plasma concentrations were 27,700 and 18,800 nmol/l for the idarucizumab 4 g (5-min) and 8 g (1-h) infusion groups, respectively.
Idarucizumab pharmacokinetics Pharmacokinetic parameters for idarucizumab for all 5-min and 1-h infusion dose groups are shown in ▶ Table 2. Peak concentrations were achieved at or shortly after the end of the 1-h or 5-min infusions. Geometric mean peak exposure (Cmax) and total exposure (AUC0–∞) both increased proportionally with dose (▶ Table 2). Peak concentrations were followed by a rapid mono- to biphasic decline in plasma concentrations (▶ Figure 1 and ▶ Figure 2). The geometric mean initial half-life was short, ranging from 39–54 min across doses. At 4 h after the end of the 5-min infusions, geometric mean idarucizumab plasma concentrations had decreased to approximately 4 % or less of peak concentrations. The terminal half-life for idarucizumab doses ≥ 600 mg ranged from geometric mean 4.5–8.1 h. Trace amounts of idarucizumab were detectable in plasma for up to 16 h after infusion of 1 g and up to 24 h after infusion of higher doses. The distribution volume of idarucizumab at steady state approximated the blood volume; the volume of distribution during the terminal phase ranged from 17.6–37.9 liters for idarucizumab doses of ≥ 600 mg.
Pharmacodynamics Baseline values for all coagulation parameters are shown in ▶Table 3. At doses of 8 g infused over 1 h and 4 g infused over 5 min, idarucizumab had no effect on the coagulation markers determined 15 min after the end of the infusion when idarucizumab plasma levels were highest (▶ Table 3). Inter-individual variability of pharmacodynamic response was low for all coagulation parameters, with coefficient of variation values ranging from 0.87–16.9 % for both time points. The lowest variability was achieved with the dTT assay (coefficient of variation range 0.87–1.80 %), followed by the TT, ECT and aPTT; the ACT showed the highest variability between individuals (▶ Table 3).
Table 2: Pharmacokinetic parameters of idarucizumab following 1-h or 5-min infusion (13 dose groups).
Idarucizumab (1 h)
Idarucizumab (5 min)
20 mg 60 mg 200 mg 600 mg 1.2 g
2g
3g
4g
6g
8g
1g
2g
4g
Subjects, N
6
6
6
5
6
12
6
6
6
5
6
6
6
AUC0–∞, nmol·h/l, gMean (gCV, %)
146 (19.8)
426 (11.6)
1950 (129)
6970 (75.4)
8780 (4.92)
14500 (15.9)
22600 (17.6)
31000 (12.9)
41200 (11.8)
63800 (15.6)
7790 (13.1)
16400 (16.8)
25800 (22.1)
AUC0–∞, norm nmol·h/l/mg, gMean (gCV, %)
7.29 (19.8)
7.11 (11.6)
9.77 (129)
11.6 (75.4)
7.32 (4.92)
7.27 (15.9)
7.53 (17.6)
7.76 (12.9)
6.87 (11.8)
7.97 (15.6)
7.79 (13.1)
8.19 (16.8)
6.46 (22.1)
Cmax, nmol/l, gMean (gCV, %)
79.9 (15.1)
257 (11.1)
809 (13.9)
2440 (13.1)
4520 (9.72)
7420 (15.1)
11700 (10.4)
15700 (15.6)
22100 (12.0)
33900 (13.2)
6360 (16.7)
13600 (23.4)
21400 (13.1)
Cmax,norm nmol/l/mg, gMean (gCV, %)
3.99 (15.1)
4.29 (11.1)
4.05 (13.9)
4.07 (13.1)
3.77 (9.72)
3.71 (15.1)
3.92 (10.4)
3.91 (15.6)
3.68 (12.0)
4.24 (13.2)
6.36 (16.7)
6.78 (23.4)
5.34 (13.1)
tmax, h median (min–max)
1.00 1.03 1.03 (0.967– (0.967– (0.967– 1.17) 1.17) 1.08)
1.10 (1.03– 1.18)
0.967 (0.967– 1.08)
0.984 1.00 1.06 1.03 1.08 0.117 0.142 (0.967– (0.967– (0.967– (0.967– (0.967– (0.0830– (0.117– 1.17) 1.05) 1.17) 1.08) 1.17) 0.167) 0.250)
0.167 (0.117– 0.250)
t1/2, h, gMean (gCV, %)
0.887 (18.1)
0.978 (12.6)
2.13 (329)
7.9 (213)
5.52 (24.1)
6.96 (31.9)
7.62 (12.0)
7.65 (12.2)
6.83 (9.80)
6.73 (4.77)
4.54 (17.9)
7.42 (33.1)
8.11 (11.1)
t1/2, 2, h, gMean (gCV, %)
0.777 (27.3)
0.746 (18.8)
0.658 (23.0)
0.725 (10.4)
0.906 (12.6)
0.782 (12.6)
0.779 (7.14)
0.796 (15.6)
0.888 (6.31)
0.850 (13.2)
0.751 (22.2)
0.773 (5.39)
0.725 (17.6)
AUC, area under curve; Cmax, maximum measured concentration in plasma; gCV, geometric coefficient of variation; gMean, geometric mean; tmax, time from dosing to maximum measured concentration; t1/2, terminal half-life; t1/2, 2, initial half-life.
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Figure 1: Geometric mean idarucizumab plasma concentration–time profiles from the start of a single infusion of 20 mg to 8 g idarucizumab for 1 h on a linear scale (A) and a semi-log scale (B).
Infusions of idarucizumab at these doses also had no effect on the ETP at the time point measured, indicating the absence of prothrombotic properties of idarucizumab (▶ Figure 3).
Safety No clinically relevant differences in the overall incidence of AEs in subjects receiving placebo or idarucizumab were observed. In total, 42 of 110 subjects (38.2 %) reported at least one AE during the treatment period (12 of 27 subjects on placebo, and 30 of 83 subjects on idarucizumab [Suppl. Table 1, available online at www. thrombosis-online.com]). The most frequently reported AEs were headache, nasopharyngitis, back pain and skin irritation (▶Table 4). There were no serious AEs, protocol-specified significant AEs, other significant AEs or AEs leading to discontinuation of trial drug during the treatment period. The majority of AEs were of mild intensity. No relationship between dose and frequency of AEs was observed. AEs assessed as drug-related by the investigator occurred in five of 110 (4.5 %) subjects (two placebo subjects and three idarucizumab subjects) during the treatment period. Of the two subjects on placebo (1-h infusion), one reported pain in extremity, and one had upper abdominal pain and chest pain. Two subjects in © Schattauer 2015
the 2-g idarucizumab (1-h) dose group reported headache (both subjects) and erythema at the infusion site (one subject), and one subject in the 8-g idarucizumab (1-h) dose group had migraine. All drug-related AEs were of mild intensity, except for the migraine; the migraine was of moderate intensity and was probably caused by the study procedure. No AEs that were considered drugrelated were reported during the follow-up period. There were no clinically relevant findings in laboratory parameters, vital signs, electrocardiogram, cardiac telemetry and physical examination. A dose-dependent, transient increase in urine protein and low-weight proteins was observed in subjects who received idarucizumab. However, there were no corresponding changes indicating acute tubular injury or loss of function, and values returned to normal range within 4–12 h after end of infusion. There were no local tolerability reactions in subjects receiving five-minute infusions of idarucizumab 1–4 g. Among subjects in the 1-h dose groups, one subject receiving 8 g idarucizumab reported swelling at the infusion site, one subject receiving 2 g idarucizumab had redness and pain at the infusion site, and another subject on placebo reported pain at the infusion site. All skin reactions were of mild intensity. No clinically relevant local skin reactions were observed in the two subjects (200 mg, 1-h infusion; and Thrombosis and Haemostasis 113.5/2015
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Figure 2: Geometric mean idarucizumab plasma concentration–time profiles from the start of a single infusion of 1 g to 4 g idarucizumab for 5 min on a linear scale (A) and a semi-log scale (B).
8 g, 1-h infusion) in whom idarucizumab was infused partly paravenously. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in 13 of 110 subjects (four of 27 subjects randomised to placebo and nine of 83 subjects randomised to idarucizumab). Most subjects with anti-idarucizumab antibodies at pre-dose
tested positive throughout the study. These antibodies were directed to the C-terminus of the Fab and not to the dabigatranbinding portion of the Fab. Three subjects with idarucizumab and one subject with placebo had a transient, low titre antibody response, which was not observed at subsequent time points. There were no AEs consistent with immunogenic reactions.
8 g idarucizumab, 1-h infusion
4 g idarucizumab, 5-min infusion
Baseline (N=6)
Baseline (N=6)
15 min postinfusion (N=5)
15 min postinfusion (N=6)
Mean ± SD, s
CV, % Mean ± SD, s
CV, % Mean ± SD, s
CV, %
Mean ± SD, s
CV, %
dTT
32.0 ± 0.3
0.871
31.5 ± 0.4
1.16
31.9 ± 0.3
0.986
31.4 ± 0.6
1.80
ECT
37.3 ± 3.8
10.2
39.2 ± 5.3
13.4
36.6 ± 1.3
3.58
37.8 ± 1.9
4.93
TT
11.9 ± 0.5
4.29
12.3 ± 0.8
6.42
11.7 ± 1.0
8.36
11.7 ± 1.0
8.46
aPTT
31.4 ± 4.9
15.5
33.4 ± 4.8
14.3
32.8 ± 3.1
9.37
31.9 ± 2.4
7.60
ACT
114 ± 19.3
16.9
110 ± 13.5
12.3
112 ± 9.0
8.00
104 ± 12.8
12.4
Table 3: Blood coagulation times determined as dTT, ECT, TT, aPTT and ACT, before and after infusion of idarucizumab.
ACT, activated clotting time; aPTT, activated partial thromboplastin time; CV, coefficient of variation; dTT, diluted thrombin time; ECT, ecarin clotting time; s, seconds; SD, standard deviation; TT, thrombin time.
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8 g, 1-h Infusion
4 g, 5-min Infusion
Figure 3: Effect of idarucizumab administered as an 8 g infusion over 1 h and a 4 g infusion over 5 min on endogenous thrombin generation potential (mean thrombin area under concentration curve [AUC]). Values were determined at baseline and 15 minutes after the end of the infusion. Error bars show standard deviation from the mean.
Discussion In this first-in-human study, idarucizumab was safe and well tolerated when administered to healthy male subjects in single rising doses from 20 mg to 8 g over 1 h or from 1–4 g over 5 min. Peak plasma concentrations of idarucizumab were achieved at the end of infusion, which would ensure immediate availability in plasma for dabigatran binding. Idarucizumab concentrations then rapidly declined to 4 % or less of peak concentrations after 4 h, with an initial half-life of ~45 min. The low volume of distribution and the observed renal excretion over the first 4-h collection interval suggest that this initial decline was dominated by renal elimination processes. As with most small proteins, a major fraction of
idarucizumab is expected to be eliminated by renal catabolism (15). The dose-dependent increase in the fraction of unchanged drug excreted into urine suggest saturation of renal tubule receptors responsible for reuptake of filtered proteins (16); these findings are consistent with studies assessing the renal reuptake of other Fabs (17, 18). In in vitro studies, equimolar concentrations of idarucizumab, i. e. 1:1 stoichiometry of dabigatran and idarucizumab, were required for complete neutralisation of the dabigatran anticoagulant effect (10). We calculated based on median peak concentrations of dabigatran seen in atrial fibrillation patients from the RE-LY study who received 150 mg dabigatran twice daily (1) that an equimolar ratio of idarucizumab to the total body load of
Table 4: Frequency of subjects with adverse events, and adverse events occurring in ≥ 2 subjects, across all dose groups of idarucizumab.
n (%)
Placebo Idarucizumab (1 h and 5 min) 20 mga 60 mga
200 mga 600 mga 1–1.2 gb 2 gc
3 ga
4 gd
6 ga
8 ga
Total
Subjects, N
27
6
6
6
5
12
18
6
12
6
6
83
Subjects with AEs
12 (44.4)
2 (33.3)
2 (33.3)
5 (83.3)
2 (40.0)
4 (33.3)
6 (33.3) 3 (50.0) 3 (25.0) 1 (16.7) 2 (33.3) 30 (36.1)
Headache
2 (7.4)
1 (16.7)
0
2 (33.3)
0
1 (8.3)
2 (11.1) 1 (16.7) 2 (16.7) 0
0
Nasopharyngitis
2 (7.4)
0
1 (16.7)
0
1 (20.0)
0
1 (5.6)
0
0
0
1 (16.7) 4 (4.8)
Back pain
1 (3.7)
0
0
0
1 (20.0)
2 (16.7)
0
1 (16.7) 0
0
0
4 (4.8)
Skin irritation
2 (7.4)
0
0
1 (16.7)
0
0
0
1 (16.7) 0
1 (16.7) 0
3 (3.6)
Catheter site pain
1 (3.7)
0
0
1 (16.7)
0
0
1 (5.6)
0
0
0
0
2 (2.4)
Pain in extremity 1 (3.7)
0
1 (16.7)
0
0
0
1 (5.6)
0
0
0
0
2 (2.4)
Diarrhoea
0
1 (16.7)
0
0
0
0
0
1 (16.7) 0
0
0
2 (2.4)
Dizziness
1 (3.7)
1 (16.7)
0
0
0
0
0
0
0
0
0
1 (1.2)
Migraine
0
0
0
0
0
1 (8.3)
0
0
0
0
1 (16.7) 2 (2.4)
Musculoskeletal stiffness
0
0
0
1 (16.7)
0
0
0
0
0
0
1 (16.7) 2 (2.4)
9 (10.8)
a1-h
infusion. bData pooled from the 1.2 g 1-h infusion group and the 1 g 5-min infusion group. cData pooled from the 2 g 1-h infusion group and the 2 g 5-min infusion group. dData pooled from the 4 g 1-h infusion group and the 4 g 5-min infusion group. Data from treatment period. AE, adverse event.
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dabigatran would be provided by a 2-g dose of idarucizumab. However, trough plasma concentrations varied more than five-fold in RE-LY (19), and higher concentrations than the median may require higher doses of idarucizumab for full reversal. Patients with bleeding may also have elevated concentrations compared with patients without major bleeding (19). In the present study, the highest doses of idarucizumab used (4 g over 5 min, and 8 g over 1 h) therefore correspond to 200 % and 400 % of the predicted dose of idarucizumab that will completely neutralise the median peak dabigatran concentrations observed in patients. Thus the expected clinical dose of 5 g is judged to be both effective and safe. Administration of idarucizumab at doses up to 8 g did not appear to result in any elevated procoagulant or anti-coagulant activity in the plasma of these healthy subjects. No effect on blood coagulation as assessed by dTT, ECT, aPTT or TT, or the bedside test ACT, at 15 min after the end of the infusion could be observed. In addition, idarucizumab did not affect the ETP. These findings are consistent with in vitro data showing no effect of idarucizumab alone (at concentrations up to 3 mg/ml) on clotting in a dTT assay and no effect on ETP (10). Also consistent with our findings, binding studies indicated that idarucizumab does not bind to known endogenous thrombin targets, despite some structural similarities to thrombin and its high affinity for dabigatran (10). The AE profile of idarucizumab revealed no unexpected or clinically relevant safety concerns, with the observed AEs mostly of mild intensity, and no relationship between idarucizumab dose and AE frequency. In addition, no clinically relevant changes in any of the safety parameters were observed. No formation of persistent new antibodies against idarucizumab was detected in these 110 subjects; however, data from a larger number of subjects are required to allow a conclusive evaluation of immunogenicity. A
What is known about this topic?
• • •
All anticoagulants carry an inherent risk of bleeding, which can be fatal in rare cases. No specific reversal agents are currently available for any of the oral anticoagulants. Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity, and is in development as a specific antidote for dabigatran.
What does this paper add?
•
•
Idarucizumab was safe and well tolerated after intravenous infusion in healthy volunteers. Its pharmacological profile met the requirement for rapid peak exposure followed by rapid elimination, with no effect on pharmacodynamic parameters when administered alone. These first-in-human data support the continued development of idarucizumab as a reversal agent for dabigatran. Idarucizumab could provide a further treatment option for use in emergency bleeding situations, if safety and efficacy in reversing dabigatraninduced anticoagulation are confirmed in further studies.
dose-dependent, transient increase in urine protein and lowweight proteins, concurrent with the transient urinary excretion of idarucizumab, may indicate saturation of tubular uptake processes for the reabsorption of proteins from the filtrate (16). While this study demonstrates the safety of idarucizumab in doses exceeding the planned clinical dose of 5 g and suggests that idarucizumab has the potential for use in patients as a rapid reversal agent for dabigatran, the study has potential limitations. The dose being tested was known to both subjects and investigators, although double-blind conditions around treatment were maintained. The objective nature of the assay results and measured plasma levels limit the potential for observer bias. However, these tests were carried out in healthy volunteers and extrapolation to a patient population with multiple morbidities is required to further assess the safety profile.
Conclusions In this first-in-human study of the specific dabigatran antidote idarucizumab, peak plasma exposure was reached quickly, followed by rapid elimination. In the absence of dabigatran, idarucizumab had no effect on coagulation parameters or ETP. Idarucizumab was safe and well tolerated at all administered doses, as either a 1-h or 5-min infusion. Acknowledgements
The study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. All authors have had full access to data and contributed to drafting the paper. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors and received no compensation related to the development of the manuscript. Medical writing assistance, supported financially by Boehringer Ingelheim Pharma GmbH & Co. KG, was provided by Mary Berrington, PhD, of PAREXEL during the preparation of this article. Conflicts of interest
S. Glund, J. Stangier, M. Schmohl, B. Lang, V. Moschetti, and J. Van Ryn are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. P. Reilly and S. Norris are employees of Boehringer Ingelheim Pharmaceuticals, Inc. S. Ramael was principal investigator of this trial and an employee of SGS Life Science Services, the contract research organisation that was funded by Boehringer Ingelheim Pharma GmbH & Co. KG to perform the clinical trial.
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