Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: a Pharmacokinetics, Pharmacodynamics, and Safety Study
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Adv Ther (2020) 37:3916–3928 https://doi.org/10.1007/s12325-020-01439-2 ORIGINAL RESEARCH Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study Zining Wang . Xia Zhao . Pengkang He . Shuqing Chen . Jie Jiang . Akiko Harada . Steven Brooks . Yimin Cui Received: May 25, 2020 / Published online: July 20, 2020 Ó The Author(s) 2020 ABSTRACT b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate Introduction: Idarucizumab is a humanized (220 mg b.i.d., oral) and idarucizumab monoclonal antibody fragment that specifically (2.5 ? 2.5 g, intravenous) 2 h after the last binds to dabigatran with high affinity and administration of dabigatran etexilate. reverses its anticoagulant effect. This study Results: The geometric mean (gMean) values of investigated the pharmacokinetics (PK) and area under the plasma concentration–time pharmacodynamics (PD) of idarucizumab in curve (AUC0–?) and maximum concentration healthy Chinese subjects at steady state of (Cmax) were 44,200 nmol h/L and 30,900 nmol/ dabigatran and explored the effect of idaru- L, respectively. An amount of 35.3 lmol of cizumab on PK and PD of dabigatran. idarucizumab, corresponding to 33.8% of the Methods: Twelve subjects received dabigatran total dose, was excreted by urine over 72 h. The etexilate treatment alone (220 mg twice daily, area under the effect (AUECabove,2–12) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted Zining Wang and Xia Zhao contributed equally to this work. thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time Digital Features To view digital features for this article (aPTT), and thrombin time (TT), which indi- go to https://doi.org/10.6084/m9.figshare.12613334. cated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse & Z. Wang Á X. Zhao Á S. Chen Á Y. Cui ( ) events reported in this study. No subject tested Department of Pharmacy, Peking University First Hospital, Beijing, China positive for anti-idarucizumab antibodies. e-mail: [email protected]; [email protected] Conclusion: Idarucizumab was well tolerated and no subject tested positive for anti-idaru- P. He Á J. Jiang cizumab antibodies in this study. PK and PD of Department of Cardiology, Peking University First Hospital, Beijing, China idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with A. Harada those in Japanese and Caucasian subjects. Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd, Kobe, Japan Clinical registration: ClinicalTrials.gov Identi- fier No. NCT03086356. S. Brooks Biostatistics and Data Sciences Department, Boehringer Ingelheim (China) Investment Co., Ltd, Shanghai, China Adv Ther (2020) 37:3916–3928 3917 Keywords: Dabigatran etexilate; Healthy long-term anticoagulation therapy (RE-LY) Chinese subjects; Idarucizumab; study, compared with warfarin, dabigatran Pharmacokinetic/pharmacodynamic; Safety etexilate demonstrated superior efficacy and similar bleeding rates with 150 mg twice daily (b.i.d.) and non-inferiority and an improved Key Summary Points bleeding profile with 110 mg b.i.d.; these ben- efits were consistent across Asian and non-Asian Why carry out this study? subgroups [6, 11]. The incidence of atrial fibrillation-related As with all anticoagulants, bleeding is the stroke has increased over the past 8 years main side effect [6, 12–14] and the RE-LY trial in China as well as the use of oral reported that major bleeding events were anticoagulation, e.g., dabigatran etexilate. observed in 3.11% of patients and life-threat- ening-bleeding events in 1.45% of patients As with all anticoagulants, bleeding is the treated with 150 mg dabigatran etexilate b.i.d. main side effect of dabigatran etexilate, [6], while 2% of the patients required an urgent which can be reversed by idarucizumab, surgery or procedure over 2 years [15]. Drug but its clinical pharmacology in Chinese discontinuation and/or transfusion of red cell subjects is limited. concentrates could be effective strategies to What was learned from the study? manage the dabigatran-associated bleeding, and further reversal of this anticoagulant effect In this study, the pharmacokinetics and could be achieved by the dabigatran-specific pharmacodynamics of idarucizumab at a reversal agent idarucizumab [16–18]. Reversal steady state of dabigatran in healthy strategies such as idarucizumab may also be Chinese subjects were comparable with indicated for anticoagulated patients with those in Japanese and Caucasians. overdose when rapid normalization is not Idarucizumab was also well tolerated and expected [19–21]. no subjects tested positive for anti- First approved in the USA in 2015, idaru- idarucizumab antibodies in Chinese cizumab is a humanized monoclonal mouse subjects. antibody fragment (Fab) that binds to dabiga- tran, thereby reversing its anticoagulant effect [18]. To date, idarucizumab has been approved in more than 55 countries worldwide, including the European Union and Japan. In June 2018, the recommended dose of 5 g, provided as two INTRODUCTION separate vials each containing 2.5 g/50 mL idarucizumab, was approved in China [22]. The Chinese population has been shown to The clinical pharmacology of idarucizumab have a slightly higher overall stroke incidence has been investigated in several phase I studies and a higher proportion of intracerebral hem- involving healthy Caucasian and Japanese sub- orrhage than the Caucasian population [1]. The jects [23–26]. A phase III study that investigated incidence of atrial fibrillation (AF)-related stroke idarucizumab in dabigatran etexilate-treated has increased significantly over the past 8 years patients with uncontrollable or life-threatening in China, and there is an increase in oral anti- bleeding or in need of an emergency surgery or coagulation use in Chinese patients with AF in procedure showed that 5 g of idarucizumab can recent years [2–5]. Dabigatran etexilate, an oral reverse the anticoagulant effect of dabigatran direct thrombin inhibitor, has been registered [17, 27]. On the basis of the results of these worldwide for the prevention of stroke in studies, idarucizumab has a low immunogenic patients with AF and for the treatment and potential [28, 29]. However, to date, the clinical secondary prevention of venous thromboem- pharmacology data of idarucizumab in Chinese bolism [6–10]. In the randomized evaluation of population has been limited. 3918 Adv Ther (2020) 37:3916–3928 The present study aims to investigate the dose on day 4. The dose was chosen to achieve pharmacokinetics (PK) and pharmacodynamics the maximum concentration of dabigatran (PD) of idarucizumab in healthy Chinese male similar to concentrations obtained after and female subjects at a steady state of dabiga- administration of dabigatran etexilate 150 mg tran and to explore the effect of idarucizumab b.i.d. to the patient population with non- on dabigatran’s PK and PD. valvular atrial fibrillation of RE-LY [6]. During the second part of the treatment period, and after a washout period of 3 days (days 5–7), METHODS subjects again received dabigatran etexilate b.i.d. for 3 days (days 8–10) and a single 220-mg This trial was conducted between 22 May 2017 dose on day 11. Idarucizumab was administered and 12 September 2017 at Peking University intravenously approximately 2 h after the last First Hospital, Beijing, China. dabigatran etexilate administration in two short infusions of 2.5 g each within a 15-min interval. Study Subjects Pharmacokinetics Assessment Healthy male and female subjects aged 18 to 45 years (body mass index at least 19 and less Blood samples for idarucizumab and dabigatran 2 than 24 kg/m ) were included. Exclusion crite- PK analysis and anti-idarucizumab antibodies ria included any illness or infection, abnormal (ADA) analysis were collected into K3-ethylen- values for prothrombin time, activated partial diaminetetraacetic acid (EDTA) anticoagulant thromboplastin time (aPTT), and platelet blood drawing vials, and centrifuged at counts that were considered as safety parame- 2000–40009g for 10 min at 4–8 °C within ters by the investigator to be clinically relevant. 30 min after the blood samples were taken. The The study was approved by the Ethics Com- plasma was divided into aliquots before being mittee for Clinical Trials, Peking University First stored at - 70 °C or below. Urine samples were Hospital, Beijing, China. All procedures per- taken cumulatively during sampling intervals formed in studies involving human participants into a polyethylene container and stored at were in accordance with the ethical standards of 4–8 °C for the remainder of that collection the institutional review board and with the interval, and finally stored at - 70 °C or below. 1964 Helsinki Declaration and its later amend- ments or comparable ethical standards, and in Idarucizumab PK Parameters accordance with the principles of Good Clinical Practice and local guidelines. Written informed consent was obtained from all individual par- Idarucizumab PK parameters Cmax (maximum ticipants prior to study enrolment. measured concentration in plasma), AUC0–? (area under the concentration–time curve in plasma over the time interval from 0 extrapo- Study Design lated to infinity), and Ae0–72 (amount elimi- nated in urine over the time interval from 0 to This was an open-label, single-center, two-part 72 h) were assessed as primary endpoints and trial conducted in one group of healthy sub- other PK parameters were calculated jects. Idarucizumab (solution for infusion) and appropriately. dabigatran etexilate (capsule) were produced AUC0–? was calculated as AUC0–? = and provided by Boehringer Ingelheim Pharma AUClast ? Ct/kz, where Ct is the last measurable GmbH & Co. KG, Biberach/Riss, Germany. concentration. AUClast was calculated using a During the first part of the treatment period, linear up–log down method. kz was calculated dabigatran etexilate was administered alone. All by linear least squares analysis using the last subjects received 220 mg dabigatran etexilate three or more non-zero plasma concentration b.i.d.