ALBERT

Description: Background: Specific reversal agents for oral anticoagulants may be necessary to manage life-threatening bleeding or prior to emergency surgical procedures. While many reversal agents are in development, idarucizumab is approved and now available commercially in many countries. Idarucizumab is a humanized antibody fragment that specifically binds to dabigatran with high affinity and has shown immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy male Caucasian volunteers. The present study investigated the safety, tolerability and pharmacokinetics of idarucizumab (part 1) and explored the effective dose of idarucizumab to reverse the dabigatran-induced anticoagulant effect (part 2) in healthy male Japanese volunteers. Methods: This was a two-part, phase I, randomized, placebo-controlled, double-blind, single-center, rising dose study. In part 1, subjects (n = 32) were randomized to receive either placebo (n = 2/dose group) or single intravenous doses of idarucizumab, 1, 2, or 4 g as a 5-minute infusion or 8 g as a 1-hour infusion (n = 6/group). In part 2, subjects (n = 48) were treated orally for 3 days with dabigatran etexilate (DE, 220 mg bid). On day 4, subjects received a final DE dose, followed a 3-day wash out period. Subjects were again treated orally for 3 days with DE, 220 mg bid. On Day 11, subjects received a final DE dose followed 2 hours later by placebo (n = 3/group) or idarucizumab (1, 2, 4, or 5 g [2.5 g followed by 2.5 g given 15 minutes apart]) as a 5-minute intravenous infusion, n = 9/group). The number of subjects with adverse events (AEs), emergence of anti-idarucizumab antibodies (ADAs), pharmacokinetics and the impact of idarucizumab on coagulation parameters were assessed (diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, and thrombin time). In addition, potential procoagulant effects were monitored as D-dimer and prothrombin fragment F1.2. Results: Idarucizumab attained a maximum concentration in plasma around the end of each infusion followed by a biphasic decline in plasma concentrations with a rapid initial phase and a longer terminal phase.. Dabigatran treatment prolonged the clotting times of all coagulation parameters. Idarucizumab infusion resulted in immediate and complete reversal of dabigatran-induced anticoagulation, reducing coagulation parameters below the upper limit of normal. The duration was dose-dependent; at 4 and 5 g of idarucizumab, complete reversal was sustained up to 72 hours, at lower doses ≤ 2 g a partial return of the anticoagulation activity of dabigatran was observed 1-2 hours after idarucizumab administration. Concentration of unbound dabigatran decreased to below the limit of quantification immediately after administration of a single dose of idarucizumab. Idarucizumab was safe and well tolerated, and no AEs were reported. There was no elevation of either D-dimer or F1.2 levels post idarucizumab as compared to levels prior to infusion in any of the dose groups. Treatment-emergent ADAs occurred in 6 of 60 patients receiving idarucizumab. Conclusion: Idarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-associated anticoagulation in healthy male Japanese volunteers. Idarucizumab was safe and well tolerated with no procoagulant effects. Disclosures van Ryn: Boehringer Ingelheim: Employment. Yasaka:Sanofi: Research Funding; Nippon Boehringer Ingelheim: Other: received lecture fees (over 1 million Yen); Bristol-Myers Squibb: Other: received lecture fees (over 1 million Yen); Bayer Yakuhin: Other: received lecture fees (over 1 million Yen); Daiichi-Sankyo: Other: received lecture fees (over 1 million Yen). Harada:Boehringer Ingelheim: Employment. Taniguchi:Boehringer Ingelheim: Employment. Imazu:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Gansser:Boehringer Ingelheim: Employment. Stangier:Boehringer Ingelheim: Employment.

Description: Abstract 2307 Introduction: Although therapy with dabigatran etexilate does not require routine blood coagulation monitoring, under some clinical scenarios (e.g., severe or life-threatening bleeding, overdose or emergency surgery) a simple assay may be valuable. The HEMOCLOT® direct thrombin inhibitors assay (HYPHEN BioMed, France, CK002K), in conjunction with calibration standards and quality controls, allows the accurate and precise determination of dabigatran concentrations within a range of 50–500 ng/mL. Calibration and standardization of the assay minimizes intra- and interlaboratory variability. The present study was conducted to confirm the accuracy and reproducibility of the HEMOCLOT® assay in samples derived from patients undergoing total hip arthroplasty taking dabigatran etexilate for the prevention of venous thromboembolism in the RE-NOVATE® II trial. Methods: Dabigatran concentrations in low- and high dabigatran quality control samples were determined by a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method (providing concentrations of 122 ng/mL and 285 ng/mL, respectively) and by back-calculation from thrombin times obtained in the calibrated HEMOCLOT® assay. Precision and accuracy of the HEMOCLOT® assay were determined by comparison of results. A total of 100 samples collected 2 hours post-dose in citrate were analyzed by both HEMOCLOT® and LC-MS/MS. The primary study endpoint was the comparison of total dabigatran concentrations determined by both methods. Results: Total assay imprecision for low dabigatran quality control samples was 2.6% coefficient of variation, with precision (repeatability) within-run 2.1%, between-run 1.4%, and between-day 0.6%. The respective values for high dabigatran samples were 2.8%, 1.8%, 2.0% and 0.9%. In the analysis of accuracy, the mean deviation of the calculated dabigatran concentration from the 122 ng/mL dabigatran sample target value was 14%, and from the 285 ng/mL dabigatran sample was –0.08%. In general, quality control sample concentrations of dabigatran were within ± 20% of the target concentration (acceptance limit). A total of 97 samples from patients provided valid data for the comparison of methods. The range of dabigatran concentrations was 68–438 ng/mL. The mean bias between the dabigatran concentrations determined by HEMOCLOT® (test) and LC-MS/MS (reference) was –8.9% (95% confidence interval –11.9 to –6.0%), with 95% limits of agreement of –37.7% to 19.8%. Conclusions: The HEMOCLOT® direct thrombin inhibitors assay in conjunction with dabigatran standards and quality controls is suitable for the precise quantitative determination of dabigatran in citrate plasma samples. The accuracy is considered acceptable for the intended use of the assay, i.e., identifying patients with very high dabigatran concentrations. Disclosures: Stangier: Boehringer Ingelheim: Employment. Eriksson:Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Huo:Boehringer Ingelheim: Consultancy. Friedman:Johnson and Johnson: Consultancy. Feuring:Boehringer Ingelheim: Employment.

Description: Introduction Oral anticoagulation is an effective therapy to prevent and treat thromboembolic events. So far, Vitamin K antagonists have been the main drug of choice. Recently, the advent of the direct oral anticoagulants (DOAC) has changed medical practice significantly; nevertheless all anticoagulants are associated with an increased risk of bleeding. Bleeding management can be achieved through established therapies; however specific antidotes are not yet available for these agents to further facilitate patient management in cases needed. Previously the dabigatran antidote (idarucizumab) has demonstrated immediate, complete and sustained reversal of dabigatran induced anti-coagulation in healthy male volunteers. In the present study it was determined whether and to what extent doses of up to 5 g idarucizumab would reverse the anticoagulant effects of dabigatran in male and female healthy mid-aged, elderly and renally impaired volunteers. In addition, it was tested whether oral intake of dabigatran etexilate 24 hrs after idarucizumab treatment could restore dabigatran related anticoagulation. It was further tested if a second administration of idarucizumab 2 months later was safe and well tolerated. Methods Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab were investigated in a randomized, double-blind, placebo controlled two-way cross-over study in 46 male and female volunteers. Dabigatran etexilate (DE), 220 mg bid in healthy subjects and 150 mg bid in subjects with mild or moderate renal impairment (CLCR60 to