ORIGINAL RESEARCH

Idarucizumab Reverses Dabigatran AnticoagulantActivity in Healthy Chinese Volunteers:A Pharmacokinetics, Pharmacodynamics, and SafetyStudy

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� The Author(s) 2020

ABSTRACT

Introduction: Idarucizumab is a humanizedmonoclonal antibody fragment that specificallybinds to dabigatran with high affinity andreverses its anticoagulant effect. This studyinvestigated the pharmacokinetics (PK) andpharmacodynamics (PD) of idarucizumab inhealthy Chinese subjects at steady state ofdabigatran and explored the effect of idaru-cizumab on PK and PD of dabigatran.Methods: Twelve subjects received dabigatranetexilate treatment alone (220 mg twice daily,

b.i.d., oral). After a washout period, the 12subjects again received dabigatran etexilate(220 mg b.i.d., oral) and idarucizumab(2.5 ? 2.5 g, intravenous) 2 h after the lastadministration of dabigatran etexilate.Results: The geometric mean (gMean) values ofarea under the plasma concentration–timecurve (AUC0–?) and maximum concentration(Cmax) were 44,200 nmol h/L and 30,900 nmol/L, respectively. An amount of 35.3 lmol ofidarucizumab, corresponding to 33.8% of thetotal dose, was excreted by urine over 72 h. Thearea under the effect (AUECabove,2–12) in thepresence and absence of idarucizumab was closeto zero for all coagulation parameters, dilutedthrombin time (dTT), ecarin clotting time(ECT), activated partial thromboplastin time(aPTT), and thrombin time (TT), which indi-cated the reversal of dabigatran anticoagulationby idarucizumab. There were no serious adverseevents reported in this study. No subject testedpositive for anti-idarucizumab antibodies.Conclusion: Idarucizumab was well toleratedand no subject tested positive for anti-idaru-cizumab antibodies in this study. PK and PD ofidarucizumab in healthy Chinese subjects at asteady state of dabigatran were comparable withthose in Japanese and Caucasian subjects.Clinical registration: ClinicalTrials.gov Identi-fier No. NCT03086356.

Zining Wang and Xia Zhao contributed equally to thiswork.

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12613334.

Z. Wang � X. Zhao � S. Chen � Y. Cui (&)Department of Pharmacy, Peking University FirstHospital, Beijing, Chinae-mail: cui.pharm@pkufh.com; cuiymzy@126.com

P. He � J. JiangDepartment of Cardiology, Peking University FirstHospital, Beijing, China

A. HaradaClinical PK/PD Department, Nippon BoehringerIngelheim Co., Ltd, Kobe, Japan

S. BrooksBiostatistics and Data Sciences Department,Boehringer Ingelheim (China) Investment Co., Ltd,Shanghai, China

Adv Ther (2020) 37:3916–3928

https://doi.org/10.1007/s12325-020-01439-2

Keywords: Dabigatran etexilate; HealthyChinese subjects; Idarucizumab;Pharmacokinetic/pharmacodynamic; Safety

Key Summary Points

Why carry out this study?

The incidence of atrial fibrillation-relatedstroke has increased over the past 8 yearsin China as well as the use of oralanticoagulation, e.g., dabigatran etexilate.

As with all anticoagulants, bleeding is themain side effect of dabigatran etexilate,which can be reversed by idarucizumab,but its clinical pharmacology in Chinesesubjects is limited.

What was learned from the study?

In this study, the pharmacokinetics andpharmacodynamics of idarucizumab at asteady state of dabigatran in healthyChinese subjects were comparable withthose in Japanese and Caucasians.

Idarucizumab was also well tolerated andno subjects tested positive for anti-idarucizumab antibodies in Chinesesubjects.

INTRODUCTION

The Chinese population has been shown tohave a slightly higher overall stroke incidenceand a higher proportion of intracerebral hem-orrhage than the Caucasian population [1]. Theincidence of atrial fibrillation (AF)-related strokehas increased significantly over the past 8 yearsin China, and there is an increase in oral anti-coagulation use in Chinese patients with AF inrecent years [2–5]. Dabigatran etexilate, an oraldirect thrombin inhibitor, has been registeredworldwide for the prevention of stroke inpatients with AF and for the treatment andsecondary prevention of venous thromboem-bolism [6–10]. In the randomized evaluation of

long-term anticoagulation therapy (RE-LY)study, compared with warfarin, dabigatranetexilate demonstrated superior efficacy andsimilar bleeding rates with 150 mg twice daily(b.i.d.) and non-inferiority and an improvedbleeding profile with 110 mg b.i.d.; these ben-efits were consistent across Asian and non-Asiansubgroups [6, 11].

As with all anticoagulants, bleeding is themain side effect [6, 12–14] and the RE-LY trialreported that major bleeding events wereobserved in 3.11% of patients and life-threat-ening-bleeding events in 1.45% of patientstreated with 150 mg dabigatran etexilate b.i.d.[6], while 2% of the patients required an urgentsurgery or procedure over 2 years [15]. Drugdiscontinuation and/or transfusion of red cellconcentrates could be effective strategies tomanage the dabigatran-associated bleeding, andfurther reversal of this anticoagulant effectcould be achieved by the dabigatran-specificreversal agent idarucizumab [16–18]. Reversalstrategies such as idarucizumab may also beindicated for anticoagulated patients withoverdose when rapid normalization is notexpected [19–21].

First approved in the USA in 2015, idaru-cizumab is a humanized monoclonal mouseantibody fragment (Fab) that binds to dabiga-tran, thereby reversing its anticoagulant effect[18]. To date, idarucizumab has been approvedin more than 55 countries worldwide, includingthe European Union and Japan. In June 2018,the recommended dose of 5 g, provided as twoseparate vials each containing 2.5 g/50 mLidarucizumab, was approved in China [22].

The clinical pharmacology of idarucizumabhas been investigated in several phase I studiesinvolving healthy Caucasian and Japanese sub-jects [23–26]. A phase III study that investigatedidarucizumab in dabigatran etexilate-treatedpatients with uncontrollable or life-threateningbleeding or in need of an emergency surgery orprocedure showed that 5 g of idarucizumab canreverse the anticoagulant effect of dabigatran[17, 27]. On the basis of the results of thesestudies, idarucizumab has a low immunogenicpotential [28, 29]. However, to date, the clinicalpharmacology data of idarucizumab in Chinesepopulation has been limited.

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The present study aims to investigate thepharmacokinetics (PK) and pharmacodynamics(PD) of idarucizumab in healthy Chinese maleand female subjects at a steady state of dabiga-tran and to explore the effect of idarucizumabon dabigatran’s PK and PD.

METHODS

This trial was conducted between 22 May 2017and 12 September 2017 at Peking UniversityFirst Hospital, Beijing, China.

Study Subjects

Healthy male and female subjects aged 18 to45 years (body mass index at least 19 and lessthan 24 kg/m2) were included. Exclusion crite-ria included any illness or infection, abnormalvalues for prothrombin time, activated partialthromboplastin time (aPTT), and plateletcounts that were considered as safety parame-ters by the investigator to be clinically relevant.

The study was approved by the Ethics Com-mittee for Clinical Trials, Peking University FirstHospital, Beijing, China. All procedures per-formed in studies involving human participantswere in accordance with the ethical standards ofthe institutional review board and with the1964 Helsinki Declaration and its later amend-ments or comparable ethical standards, and inaccordance with the principles of Good ClinicalPractice and local guidelines. Written informedconsent was obtained from all individual par-ticipants prior to study enrolment.

Study Design

This was an open-label, single-center, two-parttrial conducted in one group of healthy sub-jects. Idarucizumab (solution for infusion) anddabigatran etexilate (capsule) were producedand provided by Boehringer Ingelheim PharmaGmbH & Co. KG, Biberach/Riss, Germany.During the first part of the treatment period,dabigatran etexilate was administered alone. Allsubjects received 220 mg dabigatran etexilateb.i.d. for 3 days (days 1–3) and a single 220 mg

dose on day 4. The dose was chosen to achievethe maximum concentration of dabigatransimilar to concentrations obtained afteradministration of dabigatran etexilate 150 mgb.i.d. to the patient population with non-valvular atrial fibrillation of RE-LY [6]. Duringthe second part of the treatment period, andafter a washout period of 3 days (days 5–7),subjects again received dabigatran etexilateb.i.d. for 3 days (days 8–10) and a single 220-mgdose on day 11. Idarucizumab was administeredintravenously approximately 2 h after the lastdabigatran etexilate administration in two shortinfusions of 2.5 g each within a 15-min interval.

Pharmacokinetics Assessment

Blood samples for idarucizumab and dabigatranPK analysis and anti-idarucizumab antibodies(ADA) analysis were collected into K3-ethylen-diaminetetraacetic acid (EDTA) anticoagulantblood drawing vials, and centrifuged at2000–40009g for 10 min at 4–8 �C within30 min after the blood samples were taken. Theplasma was divided into aliquots before beingstored at - 70 �C or below. Urine samples weretaken cumulatively during sampling intervalsinto a polyethylene container and stored at4–8 �C for the remainder of that collectioninterval, and finally stored at - 70 �C or below.

Idarucizumab PK Parameters

Idarucizumab PK parameters Cmax (maximummeasured concentration in plasma), AUC0–?

(area under the concentration–time curve inplasma over the time interval from 0 extrapo-lated to infinity), and Ae0–72 (amount elimi-nated in urine over the time interval from 0 to72 h) were assessed as primary endpoints andother PK parameters were calculatedappropriately.

AUC0–? was calculated as AUC0–? =AUClast ? Ct/kz, where Ct is the last measurableconcentration. AUClast was calculated using alinear up–log down method. kz was calculatedby linear least squares analysis using the lastthree or more non-zero plasma concentrationvalues. The apparent terminal rate constant kz

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will be estimated from a regression of ln C ver-sus time over the terminal log-linear drug dis-position portion of the concentration–timeprofiles.

For idarucizumab PK, plasma samples werecollected pre-dose and post dose at 2, 10, 30min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 h.All urine voided between 0–12 and 12–24 h postdose was collected.

The idarucizumab concentrations in plasmaand urine were determined by a validatedenzyme-linked immunosorbent assay (ELISA)methods at Covance Laboratories, Inc., Chan-tilly, Virginia, USA. The method began bycoating a microtiter plate with a mouse mono-clonal anti-BI 655075 antibody (clone 5H4).After an overnight incubation, the plates wereblocked, washed, and incubated with dilutedcalibrators, quality controls, and samples whichwere previously pre-treated with dabigatran.Bound analyte was detected with anti-humanimmunoglobulin G horseradish peroxidase (IgGHRP). Tetramethylbenzidine (TMB) substratewas then added, and plates were read calori-metrically on a plate reader. The results wereanalyzed with a five-parameter logistic fit of thecalibration standard curve.

Dabigatran PK Parameters

Dabigatran is known to be conjugated withglucuronic acid to yield pharmacologicallyactive acylglucuronides. Total dabigatran (un-conjugated plus glucuronide-conjugated dabi-gatran) and unbound dabigatran (totaldabigatran neither bound to idarucizumab norto plasma proteins) were measured in plasma.Dabigatran PK parameters Ae0–74,ss of totaldabigatran (eliminated in urine over the timeinterval from 0 to 74 h at a steady state) andAUC2–12,ss of unbound dabigatran (in plasmaover the time interval from 2 to 12 h at a steadystate) on day 4 and day 11 were assessed assecondary endpoints and other PK parameterswere calculated appropriately.

Dabigatran concentrations in plasma andurine were determined by validated high-per-formance liquid chromatography–tandem massspectrometry (HPLC–MS/MS) assays at Nuvisan

GmbH, Neu-Ulm, Germany. In urine, the con-centration of unconjugated and total dabiga-tran were measured. The validated assaymethods involved direct injection on a pre-column and subsequent transfer by online col-umn switching onto the analytical RP18 col-umn. For quantification of dabigatran, thefollowing ions were recorded: 472 ? 289 amu(analyte) and 478 ? 295 amu (isotope-labelledinternal standard). In addition, ions648 ? 289 amu were monitored for dabigatranacylglucuronides.

Anti-idarucizumab Antibodies

For the analysis of anti-idarucizumab antibodies(ADAs), samples were collected at baseline, endof study (EOS), and 4-week and 3-month follow-ups. ADA in plasma was determined by a vali-dated drug-bridging electrochemiluminescence(ECL) method at Covance Laboratories, Inc.,Chantilly, Virginia, USA. Acidified samples wereadded to a mixture which contained Tris base,biotin-labeled idarucizumab, and Sulfo-TAG-la-beled idarucizumab and allowed to complexwith ADA. The labeled drug–ADA complexeswere transferred to a streptavidin plate wherethey were captured. The plate was washed toremove any nonspecific bound complexes, andread buffer (19) was added to each well of theplate. The plate was read on the Meso ScaleDiscovery (MSD) SectorTM Imager 6000.

Pharmacodynamics Assessment

The anticoagulant effect of dabigatran and itsreversal by idarucizumab were assessed bymeasuring the blood coagulation parameters,diluted thrombin time (dTT), thrombin time(TT), aPTT, and ecarin clotting time (ECT). Theblood samples were collected in citrated plasmacollection tubes and centrifuged immediately at25009g for 20 min at 4 �C. Plasma was dividedinto six separate polypropylene vials(2 9 100 lL for dTT, 2 9 150 lL for TT deter-mination, 2 9 300 lL for aPTT and ECT) andfrozen immediately at - 20 �C or below.For dTT, the parameter AUECabove,2–12 (areaunder the curve from 2 to 12 h under

Adv Ther (2020) 37:3916–3928 3919

consideration of the baseline value) was deter-mined on day 4 (dabigatran etexilate only) andon day 11 (dabigatran etexilate andidarucizumab).

In citrated plasma samples, dTT (Hemoclot,Hyphen BioMed, Neuville sur Oise, France),ECT (in-house assay, 6 U/mL ecarin; Pen-tapharm, Basel, Switzerland), TT (STA Throm-bin Reagent, Roche Diagnostics GmbH,Mannheim, Germany), and aPTT (CK Prest,Diagnostica Stago, Asnieres-sur-Seine, France)were determined by validated assays accordingto the manufacturer’s instructions at MenalGmbH (Emmendingen, Germany) [30].

Safety Assessment

All adverse events (AEs) which occurred duringthe course of the study were recorded and codedusing the Medical Dictionary for Drug Regula-tory Affairs (MedDRA, version 20.0). The fre-quency of AEs, using incidence rates, wassummarized by relationship to study drug,severity, system organ class, and preferred term.Safety was also evaluated on the basis of safetylaboratory tests (including hematology, coagu-lation parameters, clinical chemistry, and uri-nalysis), physical examination, vital signs,electrocardiogram (ECG), pO2 monitoring,local tolerability, and ADA.

Statistical Analysis

The PK, PD, and safety analyses were alldescriptive. For all parameters (dTT, TT, aPTT,and ECT), reversal to baseline was defined as acoagulation test value returning below theupper limit of normal (ULN) as determinedbased on the pre-dose values of the coagulationparameter before dabigatran drug administra-tion (primary analysis). The definition of ULNwas based on the pre-dose PD measurementsplus an appropriate tolerance (two standarddeviations, SDs) for the respective PDmeasurements.

The safety and PK analyses included all sub-jects entered. For safety evaluation (except forECG), the baseline was defined as the last

available measurement prior to the first dabi-gatran etexilate administration.

All analyses were performed using SAS� ver-sion 9.4. PK and PD parameters were calculatedusing WinNonlinTM software (professional Net-work version 6.3, Pharsight Corporation,Mountain View, CA 94041-1530, USA).

RESULTS

Subjects

A total of 12 subjects (six male and six female)were entered into the trial and received dabi-gatran etexilate and idarucizumab as plannedwithout any important protocol violations.

The mean age, height, weight, and BMI were35.6 (SD 5.8) years, 164.2 (SD 9.7) cm, 59.08 (SD6.81) kg, and 21.88 (SD 0.94) kg/m2, respec-tively. The majority of the subjects were non-smokers (10 subjects [83.3%]) and non-drinkers(9 subjects [75.0%]). Four subjects (33.3%) werereported with concomitant diagnoses whichwere no longer present at the time of screening.In all cases, the reported diagnoses were notconsidered to interfere with the analyses per-formed in this trial. Only one subject (8.3%) wasreported with concomitant therapy withmupirocin ointment to treat a bruise, whichwas considered to not interfere with the analy-ses performed in this trial.

Pharmacokinetics

Idarucizumab PK parametersAs shown in Fig. 1, the mean idarucizumabconcentration in plasma peaked at around theend of infusion with a median tmax of 0.450 hand declined rapidly with a gMean initial half-life (t1/2,2) of 0.758 h and a terminal eliminationhalf-life (t1/2) of 8.18 h after administration of2.5 ? 2.5 g idarucizumab (Table 1). The gMeanvalues of AUC0–? and Cmax in plasma were44,200 nmol h/L and 30,900 nmol/L, respec-tively. The gMean values of clearance (CL) andthe apparent volume of distribution at steadystate (Vss) were 39.4 mL/min and 6.47 L,respectively.

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The largest amount of idarucizumab wasexcreted in the first urine collection interval(0–4 h, 33.6% of dose [fe]) and the contributionof subsequent fractions was less than 0.2% ofidarucizumab dose excreted in urine, resultingin Fe0–72 of 33.8% up to 72 h (Table 1).

No apparent difference was observed for PK ofidarucizumab in male and female subjects.

Dabigatran PK ParametersAt a steady state of dabigatran in the absence ofidarucizumab, plasma concentrations ofunbound dabigatran reached a peak at 2.5 h and

Fig. 1 Plasma concentration–time profile of idarucizumab at steady state of DE. DE dabigatran etexilate

Table 1 Summary of PK parameters of idarucizumab

DE (220 mg) 1 idarucizumab (2.5 1 2.5 g) Number gMean gCV (%)

AUC0–? [nmol h/L] 12 44,200 10.1

Cmax [nmol/L] 12 30,900 9.86

tmax [h]a 12 0.450 0.417–0.517

t1/2 [h] 12 8.18 17.9

t1/2,2 [h] 12 0.758 18.3

Ae0–72 [lmol] 12 35.3 57.1

fe0–72 [%] 12 33.8 57.1

CL [mL/min] 12 39.4 10.1

Vss [L] 12 6.47 13.1

a Median (min–max)DE dabigatran etexilate, AUC area under the plasma concentration–time curve, Cmax maximum concentration, gCVgeometric coefficient of variation, gMean geometric mean, tmax time to maximum plasma concentration, t1/2 terminal half-life, t1/2,2 initial half-life, Ae amount excreted in urine, fe fraction excreted in urine, CL clearance, Vss volume of distributionat steady state

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then declined in a bi-exponential manner.Immediately after administration of the firstvial of idarucizumab, the mean plasma con-centration of unbound dabigatran decreased tobelow the limit of quantification (BLQ). Subse-quently, unbound dabigatran wasdetectable again between 26 and 74 h after thelast administration of dabigatran etexilate;however, mean concentrations remained below20 ng/mL corresponding to 42.4 nmol, i.e., athreshold at which little or no relevant antico-agulant effect would be expected [17]. Exposureto unbound dabigatran (AUC2–12,ss) decreasedto less than 1% after administration of idaru-cizumab from 1270 ng h/mL in the absence ofidarucizumab to 11.6 ng h/mL in the presenceof idarucizumab. In contrast, administration ofidarucizumab resulted in a rapid, approximatelyfourfold increase of the mean concentration oftotal dabigatran, which was inactive because ofbinding to idarucizumab.

The time profile of idarucizumab, totaldabigatran, and unbound dabigatran afteradministration of 2.5 ? 2.5 g idarucizumab ispresented in Fig. 2. Generally, as long as theconcentration of idarucizumab was higher thanthat of total dabigatran, the unbound

dabigatran concentration was BLQ. Unbounddabigatran gradually increased after total dabi-gatran concentration exceeded idarucizumabconcentration. Urinary excretion of total dabi-gatran temporarily decreased in the presence ofidarucizumab (Fe0–12,ss: 5.1% vs 3.2%, at 12 h);however, both reached a similar range ofapproximately 7% at 74 h, accounting for11.7 mg and 11.0 mg on day 4 and day 11,respectively (Fig. 3).

Pharmacodynamics

The prolongation of the coagulation times dTT,ECT, aPTT, and TT were associated withunbound dabigatran concentrations, whichpeaked at 2.5 h after administration of 220 mgdabigatran etexilate, and then decreased closeto ULN at 74 h according to the normal clear-ance of dabigatran from plasma in the absenceof idarucizumab (Fig. 4).

In contrast, immediate and complete rever-sal was observed after administration of2.5 ? 2.5 g idarucizumab in coagulation timesand mean coagulation times remained belowULN.

Fig. 2 Plasma concentration–time profile of total dabigatran, unbound dabigatran, and idarucizumab

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Fig. 3 Time profile of urinary excretion for total dabigatran. DE dabigatran etexilate, ida idarucizumab

Fig. 4 Effect of idarucizumab (2.5 ? 2.5 g) on a dilutedthrombin time (dTT), b ecarin clotting time (ECT),c activated partial thromboplastin time (aPTT), andd thrombin time (TT). Effect time profiles of coagulation

variables are overlaid with (day 11) or without idaru-cizumab (day 4). DE dabigatran etexilate, ida idarucizumab

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The reduction of coagulation times inresponse to idarucizumab administration wasfurther demonstrated by calculating the ratio ofAUECabove,2–12 in the presence of idarucizumaband the AUECabove,2–12 in the absence of idaru-cizumab. As shown in Table 2, values ofAUECabove,2–12 decreased by greater than orequal to 98% in the presence of idarucizumabcompared with those in the absence of idaru-cizumab for all coagulation parameters dTT,ECT, aPTT, and TT.

No apparent difference was observedbetween genders for the reversal demonstratedby coagulation markers.

Safety

All 12 subjects treated in this trial reported atleast one AE. On the basis of the AE onset, themost frequent AEs between the first intake ofdabigatran etexilate until the first infusion ofidarucizumab were aPTT prolonged (10 sub-jects) and prothrombin level decreased (4 sub-jects). None of these AEs were assessed as drug-related by the investigator and none requiredany therapy. The most frequent AEs with anonset between the first infusion of idaru-cizumab until the end of treatment visit werealterations in urine. This included increasedalbumin and a1-microglobulin (both for all 12subjects), proteinuria (11 subjects), and anabnormal urine electrophoresis (10 subjects).All these AEs were assessed as drug-related bythe investigator. All drug-related AEs were ofmild intensity and did not require therapy. Noother significant AEs were recorded (accordingto ICH E3). No AEs led to discontinuation of thetrial drug, and no pre-specified AEs of specialinterest (AESIs) were reported. No subject had asevere AE; all AEs were of mild intensity. There

were no deaths or other serious adverse events(SAEs) reported in this trial.

Descriptive statistics of laboratory parame-ters did not reveal any relevant changes frombaseline except for aPTT, urine a1-microglobu-lin, urine albumin, and urine IgG. Mean aPTTwas transiently prolonged compared with thebaseline value on day 4 and again on day 11,i.e., after the subjects had received dabigatranetexilate on the three preceding days. For theparameters urine a1-microglobulin, urine albu-min, and urine IgG, a transient increase of themean values from baseline was observed start-ing after administration of the first idaru-cizumab infusion (at day 11, i.e., 242 h 15 min).Mean values for urine a1-microglobulin, urinealbumin, and urine IgG returned to baselinelevels on the following day. However, individ-ual subjects also had slightly elevated levels ofurine a1-microglobulin or urine IgG at latertime points. There were no clinically relevantfindings with respect to vital signs. Local toler-ability of the infusion was good.

No subject tested positive for ADA at anytime point up to 3 months after idarucizumabadministration.

DISCUSSION

This study investigated the PK and PD ofidarucizumab in healthy Chinese male andfemale subjects for the first time. Consistentwith the previous studies in Caucasian andJapanese subjects, immediate and completereversal was observed in Chinese subjects afteradministration of 2.5 ? 2.5 g idarucizumab atthe steady state of dabigatran. This was sus-tained over the entire observation period of72 h [23–25]. Idarucizumab was well toleratedby Chinese subjects.

Table 2 Mean ratio for the coagulation measurements dTT, ECT, aPTT, and TT

Ratio (N = 12, 12, 12, 12) dTT ECT aPTT TT

AUECabove;2�12 with idarucizumabAUECabove;2�12 without idarucizumab

[SD] 0.01 [0.017] 0.02 [0.017] 0.02 [0.034] 0.00 [0.007]

SD standard deviation, AUEC area under the effect curve

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The overall PK profile of idarucizumab wassimilar among Chinese, Japanese, and Cau-casian subjects [23–25]. However, urinaryexcretion was slightly higher in Chinese sub-jects compared with Japanese subjects, whileother parameters were similar to those of Japa-nese subjects. Taking into consideration thehigh interindividual variability in Chinese sub-jects as well as the overlap of individual valuesbetween Chinese and Japanese subjects, thedifference is not considered to be clinicallyrelevant.

Exposure to total dabigatran was comparablebetween Chinese and Japanese subjects whenonly male subjects were compared. Of note,exposure was approximately 20% higher infemale subjects than in male subjects in thisstudy, which is in line with known PK charac-teristics of dabigatran [31].

Peak idarucizumab was achieved at the endof infusion, and resulted in a rapid reduction ofunbound dabigatran in plasma. Immediate,complete, and sustained reversal was alsodemonstrated with 5 g of idarucizumab inJapanese and Caucasian healthy volunteers[24, 25]. Therefore, it is concluded that there isno meaningful difference in PD of idaru-cizumab in Chinese subjects compared withCaucasian and Japanese subjects. Consistentwith other countries, the dose of 5 g was alsoapproved in China.

Overall, idarucizumab and dabigatran etexi-late were well tolerated by Chinese subjects inthis trial. During treatment with dabigatranetexilate only, the most frequently reported AEswere related to anticoagulation. Accordingly,analysis of laboratory parameters revealed atransient prolongation of aPTT after the sub-jects had received dabigatran etexilate. Thisprolongation of aPTT may indicate overcoagu-lation, and the reported AEs of coagulationparameters were consistent with the mecha-nism of action of dabigatran etexilate as anti-coagulant, and none of them were assessed asidarucizumab-related by the investigator.Increase of urinary protein after idarucizumabadministration was considered to be drug-re-lated. According to the reported AEs, the anal-ysis of laboratory parameters also revealed atransient increase in urinary proteins after

administration of the first idarucizumab infu-sion. This has also been observed in the previ-ous phase I trials and likely indicates saturationof the tubular uptake processes for the reab-sorption of small proteins from the filtrate [32].The most frequent AEs for idarucizumab-treatedsubjects in the previous phase I trials wereheadache, nasopharyngitis, back pain, and skinirritation, none of which were reported in thistrial [23]. There were no clinically relevantfindings with respect to vital signs. Local toler-ability of the infusion was good. Idarucizumabwas not immunogenic in this trial.

Limitations of this study include the rela-tively limited number of subjects assessed andthe fact that only healthy subjects were inclu-ded. A phase III study (ClinicalTrials.govNCT03343704) in Chinese subjects is currentlyongoing to assess the effect of idarucizumab at adose of 5 g on the anticoagulant effect of dabi-gatran in patients who have either uncontrolledbleeding requiring urgent medical interventionor who require emergency surgery or proceduresnecessitating rapid reversal of the anticoagulanteffect of dabigatran.

CONCLUSION

Administration of idarucizumab (two intra-venous administrations of 2.5 g each, with a15-min interval) after dabigatran dosing to asteady state resulted in immediate, complete,and sustained reversal of dabigatran-inducedanticoagulant effect in healthy Chinese sub-jects. The overall PK and PD of idarucizumab inChinese subjects in this study were similar tothose in Japanese and Caucasian subjects. InChinese subjects, idarucizumab was well toler-ated and no subject tested positive for anti-idarucizumab antibodies.

ACKNOWLEDGEMENTS

Boehringer Ingelheim (China) Investment Co.,Ltd. was given the opportunity to review themanuscript content for medical and scientificaccuracy and intellectual property considera-tions. The authors wish to thank Yu Wang for

Adv Ther (2020) 37:3916–3928 3925

her statistical contributions. The authors alsothank the participants of the study.

Funding. The study and the Rapid Servicefee for this manuscript were funded by Boeh-ringer Ingelheim (China) Investment Co., Ltd.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Medical Writing and Editorial Assis-tance. Medical writing assistance was providedby Ningning Dong of Boehringer Ingelheim(China) Investment Co., Ltd.

Disclosures. Zining Wang, Xia Zhao, Peng-kang He, Shuqing Chen, Jie Jiang and YiminCui have nothing to disclosure, Akiko Haradaand Steven Brooks are employees of BoehringerIngelheim.

Compliance with Ethical Guidelines. Thestudy was approved by the Ethics Committeefor Clinical Trials, Peking University FirstHospital, Beijing, China. All procedures per-formed in studies involving human participantswere in accordance with the ethical standards ofthe institutional review board and with the1964 Helsinki Declaration and its later amend-ments or comparable ethical standards, and inaccordance with the principles of Good ClinicalPractice and local guidelines. Written informedconsent was obtained from all individual par-ticipants prior to study enrolment.

Data Availability. Boehringer Ingelheim iscommitted to responsible sharing of redactedclinical study reports, related clinical docu-ments, and de-identified patient-level clinicalstudy data after drug approval or after termi-nation of the drug development program. Thedatasets generated for this study can be accessedand analyzed via application through https://www.vivli.org/.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Tsai C-F, Thomas B, Sudlow CL. Epidemiology ofstroke and its subtypes in Chinese vs white popu-lations: a systematic review. Neurology. 2013;81:264–72.

2. Guo Y, Tian Y, Wang H, Si Q, Wang Y, Lip GY.Prevalence, incidence, and lifetime risk of atrialfibrillation in China: new insights into the globalburden of atrial fibrillation. Chest. 2015;147:109–19.

3. Chang S-S, Dong J-Z, Ma C-S, et al. Current statusand time trends of oral anticoagulation use amongChinese patients with nonvalvular atrial fibrilla-tion: the Chinese atrial fibrillation registry study.Stroke. 2016;47:1803–10.

4. Wang-Longde LJ, Yi Y, Peng B, Wang Y. The pre-vention and treatment of stroke still face hugechallenges—brief report on stroke prevention andtreatment in China, 2018. Chin Circ J. 2019;34:105–19.

5. Ma C, Li Q. GW28-e1105 Changes in oral antico-agulation treatment after dabigatran availability inChina: the GLORIA-AF Registry Program. J Am CollCardiol. 2017;70(16 Supplement):C53.

6. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabiga-tran versus warfarin in patients with atrial fibrilla-tion. N Engl J Med. 2009;361:1139–51.

3926 Adv Ther (2020) 37:3916–3928

7. Schulman S, Kearon C, Kakkar AK, et al. Dabigatranversus warfarin in the treatment of acute venousthromboembolism. N Engl J Med. 2009;361:2342–52.

8. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treat-ment of acute venous thromboembolism withdabigatran or warfarin and pooled analysis. Circu-lation. 2014;129:764–72.

9. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA,Wallentin L. Newly identified events in the RE-LYtrial. N Engl J Med. 2010;363:1875–6.

10. Schulman S, Kearon C, Kakkar AK, et al. Extendeduse of dabigatran, warfarin, or placebo in venousthromboembolism. N Engl J Med. 2013;368:709–18.

11. Hori M, Connolly SJ, Zhu J, et al. Dabigatran versuswarfarin: effects on ischemic and hemorrhagicstrokes and bleeding in Asians and non-Asians withatrial fibrillation. Stroke. 2013;44:1891–6.

12. Granger CB, Alexander JH, McMurray JJ, et al.Apixaban versus warfarin in patients with atrialfibrillation. N Engl J Med. 2011;365:981–92.

13. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxabanversus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011;365:883–91.

14. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxa-ban versus warfarin in patients with atrial fibrilla-tion. N Engl J Med. 2013;369:2093–104.

15. Douketis JD, Healey JS, Brueckmann M, et al.Urgent surgery or procedures in patients takingdabigatran or warfarin: analysis of perioperativeoutcomes from the RE-LY trial. Thromb Res.2016;139:77–81.

16. Majeed A, Hwang H-G, Connolly S. Managementand outcomes of major bleeding during treatmentwith dabigatran or warfarin. J Vasc Surg. 2014;59:871–2.

17. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idaru-cizumab for dabigatran reversal. N Engl J Med.2015;373:511–20.

18. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI.Idarucizumab: the antidote for reversal of dabiga-tran. Circulation. 2015;132:2412–22.

19. Steffel J, Verhamme P, Potpara TS, et al. The 2018European Heart Rhythm Association PracticalGuide on the use of non-vitamin K antagonist oralanticoagulants in patients with atrial fibrillation:executive summary. Eur Heart J. 2018;2:1231–42.

20. Baugh CW, Levine M, Cornutt D, et al. Anticoagu-lant reversal strategies in the emergency depart-ment setting: recommendations of amultidisciplinary expert panel. Ann Emerg Med.2019. https://doi.org/10.1016/j.annemergmed.2019.09.001.

21. Expert Committee of Stroke Prevention Project—National Health Commission of the People’sRepublic of Chinese, Chinese Society of Pacing andElectrophysiology Expert Committee, ChineseCollege Society of Arrhythmia. Expert consensus onclinical application of idarucizimab-dabigatranspecific antagonist. Chin J Cardiac Arrhyth.2020;24:113–22.

22. China National Medical Products Administration.Idarucizumab injection, S2018001286980023000365 Boehringer Ingelheim Interna-tional GmbH [Internet]. 2020. Available from:http://app1.nmpa.gov.cn/. Accessed 31 Jan 2020.

23. Glund S, Moschetti V, Norris S, et al. A randomisedstudy in healthy volunteers to investigate thesafety, tolerability and pharmacokinetics of idaru-cizumab, a specific antidote to dabigatran. ThrombHaemost. 2015;114:943–51.

24. Glund S, Stangier J, Schmohl M, et al. Safety, tol-erability, and efficacy of idarucizumab for thereversal of the anticoagulant effect of dabigatran inhealthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet.2015;386:680–90.

25. Yasaka M, Ikushima I, Harada A, et al. Safety,pharmacokinetics and pharmacodynamics ofidarucizumab, a specific dabigatran reversal agentin healthy Japanese volunteers: a randomizedstudy. Res Pract Thromb Haemost. 2017;1:202–15.

26. Glund S, Stangier J, van Ryn J, et al. Effect of ageand renal function on idarucizumab pharmacoki-netics and idarucizumab-mediated reversal ofdabigatran anticoagulant activity in a randomized,double-blind, crossover phase Ib study. Clin Phar-macokinet. 2017;56:41–544.

27. Pollack CV Jr, Reilly PA, Bernstein R, et al. Designand rationale for RE-VERSE AD: a phase 3 study ofidarucizumab, a specific reversal agent for dabiga-tran. Thromb Haemost. 2015;114:198–205.

28. Norris S, Ramael S, Ikushima I, et al. Evaluation ofthe immunogenicity of the dabigatran reversalagent idarucizumab during phase I studies. Br J ClinPharmacol. 2017;83:1815–25.

29. Glund S, Coble K, Gansser D, et al. Pharmacoki-netics of idarucizumab and its target dabigatran inpatients requiring urgent reversal of the

Adv Ther (2020) 37:3916–3928 3927

anticoagulant effect of dabigatran. J Thromb Hae-most. 2019;17(8):1319–28.

30. Stangier J, Feuring M. Using the HEMOCLOT directthrombin inhibitor assay to determine plasmaconcentrations of dabigatran. Blood Coagul Fibri-nol. 2012;23:138–43.

31. Stangier J. Clinical pharmacokinetics and pharma-codynamics of the oral direct thrombin inhibitor

dabigatran etexilate. Clin Pharmacokinet. 2008;47:285–95.

32. Reilly PA, van Ryn J, Grottke O, Glund S, Stangier J.Idarucizumab, a specific reversal agent for dabiga-tran: mode of action, pharmacokinetics and phar-macodynamics, and safety and efficacy in phase 1subjects. Am J Med. 2016;129:S64–S72.

3928 Adv Ther (2020) 37:3916–3928