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

ABSTRACT: BACKGROUND:Idarucizumab is a monoclonal antibody fragment that reverses dabigatran anticoagulation. Pharmacokinetics (PK) of idarucizumab have been described in healthy, elderly, or renally impaired (RI) volunteers, but PK data in patients are lacking. OBJECTIVES:This analysis describes the PK of idarucizumab and its target dabigatran in bleeding/surgical patients. PATIENTS AND METHODS:Results from the Reversal Effects of Idarucizumab on Active Dabigatran study, a prospective, multicenter, single-arm study demonstrated the reversal of dabigatran anticoagulation by idarucizumab in patients with uncontrollable bleeding (group A) or who needed urgent surgery (group B). Idarucizumab and unbound dabigatran concentrations, immunogenicity, and pharmacodynamics were assessed. RESULTS:Total and unbound dabigatran levels at baseline were 165 ng/mL vs 110 ng/mL and 103 ng/mL vs 69.5 ng/mL in group A and B patients, respectively. Maximum plasma concentrations and area under the curves (AUC0-24 ) of idarucizumab in group A vs B, respectively, were 24 900 nmol/L vs 25 000 nmol/L and 76 600 nmol/h/L vs 68 000 nmol/h/L. Idarucizumab AUC0-24 increased by 38% in mild, 90% in moderate, and 146% in severe RI patients vs normal renal function. Hepatic impairment or geographical region had no relevant effect on idarucizumab PK. Idarucizumab immediately decreased unbound dabigatran concentration (<20 ng/mL). A linear correlation was observed between unbound dabigatran and diluted thrombin time and ecarin clotting time. Antidrug antibody titers were low (1-64 at day 30; 0-16 at day 90) and had no impact on idarucizumab PK and pharmacodynamics. CONCLUSION:Idarucizumab PK in target patients was consistent with phase I data. Patient characteristics had no impact on PK, whereas RI increased the exposure of idarucizumab and dabigatran. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov NCT02104947.

SUBMITTER: Glund S

PROVIDER: S-EPMC6852568 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Glund Stephan S Coble Kelly K Gansser Dietmar D Stangier Joachim J Hoermann Karin K Pollack Charles V CV Reilly Paul P

Journal of thrombosis and haemostasis : JTH 20190618 8

<h4>Background</h4>Idarucizumab is a monoclonal antibody fragment that reverses dabigatran anticoagulation. Pharmacokinetics (PK) of idarucizumab have been described in healthy, elderly, or renally impaired (RI) volunteers, but PK data in patients are lacking.<h4>Objectives</h4>This analysis describes the PK of idarucizumab and its target dabigatran in bleeding/surgical patients.<h4>Patients and methods</h4>Results from the Reversal Effects of Idarucizumab on Active Dabigatran study, a prospecti ...[more]

PMID: 31050868

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Project description:Idarucizumab is the first targeted antidote of dabigatran, a direct oral anticoagulant used for prevention and treatment of venous thromboembolism and prevention of stroke in atrial fibrillation. Idarucizumab is a humanized fragment of a monoclonal antibody, which binds dabigatran reversibly with high affinity and, when administered intravenously, immediately neutralizes its anticoagulant effect. It is rapidly cleared by the kidney with captured dabigatran. In Phase I and II trials, no significant adverse events have been reported. Specifically, idarucizumab has no anticoagulant or procoagulant effect by itself. Idarucizumab is currently being evaluated in an ongoing Phase III trial, in patients treated with dabigatran presenting with severe active bleeding or requiring emergency surgery or an invasive procedure and are at high risk of bleeding. The results of the interim analysis confirm the ability of idarucizumab to neutralize dabigatran instantaneously, without rebound effect, except in rare patients with very high baseline levels of anticoagulant. Although not definitely proving clinical efficacy, due to the noncontrolled design of the trial and the heterogeneity of patient conditions, these promising results on an intermediate criterion with strong rationale have led to the approval of idarucizumab for these indications. However, several questions are unresolved. First, activity measurement of dabigatran in blood, useless in current practice, could be useful to guide the treatment and avoid over- or underutilization of the antidote; but so far, it has not been largely available in real time. Second, the translation of anticoagulant neutralization to an effect on mortality and better outcome is highly dependent on the global management of these patients, especially rapid diagnosis, supportive care, and easy access to antidote administration. Although idarucizumab represents a remarkable achievement in drug design and development, whether it will be an important step toward improved safety of patients treated with dabigatran in the real world will have to be demonstrated in the postmarketing phase.

Project description:IntroductionIdarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein.MethodsThis multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT).ResultsThe final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%.ConclusionsThe final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan.Trial registrationThis study is registered with ClinicalTrials.gov (NCT02946931).

Dataset Information

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

Publications

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

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