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Original Article
Clinical Pharmacology
in Drug Development
2021, 0(0) 1–9
© 2021 Daiichi Sankyo Inc. Clinical
Pharmacology in Drug Development
published by Wiley Periodicals LLC
on behalf of American College of
Clinical Pharmacology
DOI: 10.1002/cpdd.1050
Edoxaban Exposure in Patients With
Atrial Fibrillation and Estimated
Creatinine Clearance Exceeding
100 mL/min
Ophelia Yin1, Tarundeep Kakkar1, Anil Duggal1, Masakatsu Kotsuma1, Minggao Shi1,
Hans Lanz2, and Michael A. Grosso1
Abstract
Edoxaban 60 mg is approved for stroke prevention in patients with atrial brillation (AF) not fullling any dose-reduction
criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmaco-
dynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance
(creatinine clearance >100 mL/min) over 12 months.Primary PK and pharmacodynamics end points were plasma edox-
aban exposure and anti–factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady
state. Efcacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and
major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and
75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted
in the population PK model; anti–factor Xa concentration correlated with edoxaban exposure. Rates of composite and
individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60-75 mg)
resulted in ≈25% exposure increase in the 75-mg group. Higher exposure was not associated with reduced stroke risk
in patients with AF with high renal clearance.
Keywords
anticoagulants, atrial brillation, hemorrhage, pharmacokinetics, stroke
Direct oral anticoagulants (DOACs)—including dabi-
gatran, apixaban, rivaroxaban, and edoxaban—are
preferred over vitamin K antagonists for the prevention
of stroke in patients with nonvalvular atrial brillation
(AF); unlike vitamin K antagonists, DOACs do not
need routine anticoagulation monitoring.1,2 Edoxa-
ban 60 mg once daily—dose reduced to 30 mg once
daily in patients meeting dose-reduction criteria—was
approved for the prevention of stroke and systemic
embolic events (SEEs) based on the results of the
phase 3 Effective Anticoagulation with Factor Xa
Next Generation in Atrial Fibrillation Thrombolysis
in Myocardial Infarction 48 (ENGAGE AF-TIMI 48)
study.3In this study, edoxaban was noninferior to well-
managed warfarin for the prevention of stroke/SEEs
and was associated with less major bleeding and
cardiovascular (CV)-related death.3Although war-
farin (specically S-warfarin) is mainly eliminated via
CYP2C9-mediated metabolism with minimal contri-
bution of renal clearance, edoxaban, like all other
DOACs, is partially eliminated via the kidney, with
≈50% renal clearance (dabigatran 80% renally cleared,
rivaroxaban 35%, and apixaban 27%).4,5 Given the
high renal clearance, it was postulated that edoxaban
exposure may be lower in patients with high creatinine
clearance (CrCL >100 mL/min); thus, efcacy could
hypothetically be lower in this subpopulation.
The impact of renal function on response to edox-
aban was explored in subgroup analyses by Bohula et
al of the ENGAGE AF-TIMI 48 study (ENGAGE
AF).6It was noted that in patients with AF with
CrCL >95 mL/min, there was a trend toward de-
creased relative efcacy of edoxaban 60 mg once daily
1Daiichi Sankyo Inc ., Basking Ridge, New Jersey, USA
2Daiichi Sankyo Europe GmbH, Munich, Germany
This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial-NoDerivs License,
which permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modications
or adaptations are made.
Submitted for publication 1 September 2021;accepted 27 October 2021.
Corresponding Author:
Masakatsu Kotsuma, PhD, Daiichi Sankyo Inc., 211 Mount Airy Road,
Basking Ridge, NJ 07920
(e-mail: mkotsuma@dsi.com)
2Clinical Pharmacology in Drug Development 2021, 0(0)
compared with warfarin (stroke/SEE hazard ratio 1.36;
95%CI, 0.88-2.10; P=0.17), although the absolute
event rate in the edoxaban 60-mg subgroup was low
(1.1%/year).6However, it is important to note that in
the ENGAGE AF study, patients in the warfarin treat-
ment group with high CrCL had substantially lower is-
chemic stroke event rates than, and not consistent with,
the published warfarin ischemic stroke event rates in
this subpopulation in the other 3 major DOAC AF piv-
otal trials.3,7–10 Thus, the observed unfavorable hazard
ratio for the stroke event rate in ENGAGE AF in pa-
tients treated with edoxaban 60 mg once daily relative
to warfarin in this limited select subgroup of patients
with CrCL >95 mL/min appears driven by a surpris-
ingly low event rate for the warfarin arm.3
To further characterize the impact of high CrCL
on edoxaban exposure, this prospective study was con-
ducted to compare the drug exposure of edoxaban
60 mg once daily vs edoxaban 75 mg once daily in pa-
tients with AF who were anticoagulant-naïve and had
aCrCL>100 mL/min.
Methods
Study Design
This was a prospective, randomized, double-blind study
with evaluation of end points by an independent clin-
ical event committee. Patients were randomized (1:1)
via an interactive web/voice response system to receive
either edoxaban 75 mg once daily or edoxaban 60 mg
once daily. Patients in both arms were treated for up to
12 months with a 2- to 4-week follow-up period. Treat-
ment interruptions were discouraged but could occur
due to an adverse event (AE) or other medical reasons.
No edoxaban dose reductions were allowed in the study,
and no patients who met standard labeling criteria for
edoxaban dose reduction were enrolled.
The on-treatment period was dened as the time dur-
ing which patients were taking the study drug through
up to 3 days after their last dose. The overall study pe-
riod was the time from the date of the rst dose of the
study drug to the follow-up visit. For patients without
a follow-up visit, the overall study period was dened
as the nal dose plus 28 days. A summary of the study
design is presented in Figure 1.
The protocol and all study documents were approved
by the appropriate institutional review boards and inde-
pendent ethics committees. The full list of study sites,
the majority of which were in eastern Europe, and their
corresponding approval committee is in Table S1. This
study was conducted in accordance with the Good Clin-
ical Practice standards for drugs and the ethical princi-
ples specied in the Declaration of Helsinki. Informed
consent was obtained from all patients before enroll-
ment.
Figure 1. Study design. The goal was to randomize ≈600 pa-
tients (300 per treatment arm—edoxaban 60 mg once daily
or edoxaban 75 mg once daily) with a treatment duration of
12 months. CHADS2indicates stroke risk stratication scheme
for patients with atrial brillation (congestive heart failure, hy-
pertension, age, diabetes, and previous stroke); CrCL, creatinine
clearance; NVAF, nonvalvular atrial brillation; R, randomization.
Patient Population
Patients were required to have a diagnosis of nonva-
lvular AF documented by any electrical tracing within
the prior 12 months and a CrCL >100 mL/min (cal-
culated by the Cockcroft-Gault formula),11 and pa-
tients were required to be anticoagulant-naïve (dened
as having received no dose of any oral anticoagulants
for 30 days before randomization) with a stroke risk
stratication scheme for patients with atrial brilla-
tion (CHADS2)scoreof≥2. Patients with an indi-
cation for an edoxaban dose reduction (body weight
<60 kg, CrCL <50 mL/min, or the use of concomitant
P-glycoprotein inhibitors) were excluded. Additional
exclusion criteria included concomitant medication use
such as nonstudy anticoagulants, or chronic oral, or
parenteral nonaspirin/nonsteroidal anti-inammatory
drugs for ≥4 days/week. A complete list of exclusion
criteria is summarized in Table S2.
Study Objectives and Assessments
The primary pharmacokinetic (PK) parameters were
the minimum and average edoxaban plasma concen-
trations at steady state; anti-factor Xa (FXa) activity
was the primary pharmacodynamic (PD) parameter.
PK/PD samples were collected before dosing, 1 to
2 hours after dosing, and 4 to 8 hours after dosing on
days 30, 90, and 360 in the lithium heparin tube (for
PK) and the sodium citrate tubes (for PD). Edoxaban
plasma concentration was analyzed using a validated
liquid chromatographic–tandem mass spectromet-
ric method in Q2 Solutions (Ithaca, New York).12
Anti-FXa levels were measured at Medpace Research
Yin et al 3
Laboratory (Cincinnati, Ohio) using a commercially
available anti-FXa activity assay (STA-Liquid Anti-Xa;
Diagnostica Stago, Asnières sur Seine, France) with
an edoxaban-specic setup using the STA-Edoxaban
Calibrator and STA-Edoxaban Control on the STA-R
analyzer (Diagnostica Stago).13
To account for variability in PK parameters due to
sample collection within time windows rather than at
precise time points in the treatment arms, edoxaban
steady-state PK values were estimated by applying a
previously developed population PK (popPK) model
for edoxaban that used pooled data from 13 phase 1
studies along with the phase 3 study.14 This popPK
model included body weight, race (Asian vs non-
Asian), health status (healthy patients vs patients with
nonvalvular AF), CrCL (mL/min), and P-glycoprotein
inhibitor as covariates on relevant PK parameters.
Model-estimated steady-state concentrations were used
to make precise and adequate comparisons of PK expo-
sure parameters between the 2 doses.
Clinical efcacy and safety outcomes events were
tabulated and reported. Efcacy outcomes included the
composite of stroke, transient ischemic attack (TIA),
and SEEs; the composite of ischemic stroke, TIA, and
SEEs; and the composite of stroke and/or TIA, SEEs,
myocardial infarction, CV death, and major bleeding.
Secondary safety outcomes included the incidence of
major (including intracranial) and clinically relevant
nonmajor (CRNM) bleeding, and all bleeding events
that were categorized as major, CRNM, or nuisance
bleeding; AEs of special interest included combined el-
evations of aminotransferases and bilirubin (alanine or
aspartate aminotransferase ≥3 times the upper limit of
normal and total bilirubin ≥2 times the upper limit
of normal). All investigator-reported clinical outcome
events were adjudicated by an independent panel of
experts without knowledge of the study treatment.
The adjudicated bleeding events were dened as ma-
jor bleeding, CRNM bleeding, nuisance bleeding, or
no bleeding event, based on International Society on
Thrombosis and Haemostasis classication.
Statistical Analysis
Continuous data were summarized with descriptive
statistics. Categorical data were summarized with fre-
quency counts and percentages. The percentages were
calculated based on the total number of patients in each
treatment group and analysis category.
The safety analysis set included all patients who were
randomized and who received at least 1 dose of the
study drug. The PK analysis set (PKAS) included all
patients in the safety analysis set who received edoxa-
ban and had at least 1 postdose PK concentration mea-
surement. The PD analysis set included all patients in
the safety analysis set who had at least 1 predose PD
assessment and at least 1 postdose PD assessment. The
modied intent-to-treat (mITT) analysis set included all
randomized patients who received at least 1 dose of the
study drug.
Results
Patient Disposition and Demographics
Overall, 607 patients were randomized to edoxaban
60 mg once daily or edoxaban 75 mg once daily (303
in the edoxaban 60 mg once-daily arm and 304 in
the edoxaban 75 mg once-daily arm). The majority
of randomized patients (98.2% [596/607]) completed
the study, with similar proportions of completing pa-
tients in both treatment groups. Eleven patients with-
drew from the study (10 due to death; 1 patient with-
drew from the study after 173 days). No patients were
lost to follow-up.
The demographics and baseline clinical charac-
teristics were well balanced between treatment arms
(Table 1). The demographics and baseline character-
istics were predominately younger (median age, 61),
more likely men (72%), with higher body mass index
(median, 34.6) and more extensive medical history of
congestive heart failure, hypertension, and diabetes
mellitus (Table 1) than the overall AF population in
ENGAGE AF-TIMI 48.3Of note, the demographics
and baseline characteristics of patients in this study
were similar to the patients with high CrCL enrolled in
ENGAGE AF-TIMI 48 (Table S4). Five patients had
an initial CrCL >100 mL/min via local lab measure-
ment at randomization but were subsequently found to
have CrCL <100 mL/min via central lab measurement
(Table 1); the CrCL for these patients ranged from 92 to
100 mL/min. Of these 5 patients, 1 received edoxaban
60 mg once daily, and 4 received edoxaban 75 mg once
daily. None experienced a stroke, bleeding event, or
serious AE during the study.
Pharmacokinetic End Points
The PKAS included 298 patients randomly assigned to
edoxaban 60 mg once daily and 297 patients randomly
assigned to edoxaban 75 mg once daily. Figure S1 shows
the observed edoxaban plasma concentrations before
dosing, 1 to 2 hours after dosing, and 4 to 8 hours af-
ter dosing on days 30, 90, and 360 of the on-treatment
periods for both treatment arms. As expected, the re-
sulting measured actual plasma concentrations showed
large variability, partly due to noise from different
sampling times within the specied collection window.
The popPK model adequately described the observed
steady-state concentrations during the on-treatment
period among patients included in the PKAS (Figure
S2). The model-estimated steady-state edoxaban expo-
sure was ≈25% higher in patients receiving 75 mg once
4Clinical Pharmacology in Drug Development 2021, 0(0)
Ta b l e 1.Demographic and Baseline Clinical Characteristics (mITT Analysis Set)
Edoxaban
60 mg Once Daily (n =303)
Edoxaban
75 mg Once Daily (n =303) Overall (N =606)
Age, y
Mean (SD) 60.9 (8.1) 60.4 (8.4) 60.6 (8.2)
Median (min-max) 61.0 (32-80) 61.0 (32-82) 61.0 (32-82)
<65, n (%) 195 (64.4) 201(66.3) 396 (65.3)
65 to <75, n (%) 97 (32.0) 91(30.0) 188 (31.0)
≥75, n (%) 11 (3.6) 11 (3.6) 22 (3.6)
Male, n (%) 215(71.0) 221(72.9) 436 (71.9)
BMI, kg/m2
Mean (SD) 35.4 (5.8) 35.3 (6.4) 35.4 (6.1)
Median (min-max) 35.1(23.2-55.2) 34.4 (22.0-58.3) 34.6 (22.0-58.3)
<30, n (%) 47 (15.5) 55 (18.2) 102 (16.8)
≥30 to <35, n (%) 102 (33.7) 113 (37.3) 215 (35.5)
≥35, n (%) 154 (50.8) 133 (43.9) 287 (47.4)
CrCL, mL/min
Mean (SD) 128.7 (24.2) 129.4 (28.0) 129.0 (26.2)
Median (min-max) 123.4 (100.0-250.8) 122.3 (92.0-295.8) 122.5 (92.0-295.8)
≤100, n (%) 1(0.3) 4 (1.3) 5 (0.8)
>100 to ≤120, n (%) 134 (44.2) 137 (45.2) 271(44.7)
>120, n (%) 168 (55.4) 162 (53.5) 330 (54.5)
Atrial brillation type, n (%)
Paroxysmal 122 (40.3) 134 (44.2) 256 (42.2)
Persistent 87 (28.7) 82 (27.1)169 (27.9)
Permanent 94 (31.0) 87 (28.7) 181(29.9)
CHADS2
Mean (SD) 2.5 (0.8) 2.5 (0.8) 2.5 (0.8)
Median (min-max) 2.0 (2.0-5.0) 2.0 (1.0-5.0) 2.0 (1.0-5.0)
<2, n (%) 0 1(0.3) 1(0.2)
2, 3, n (%) 268 (88.4) 270 (89.1) 538 (88.8)
>3, n (%) 35 (11.6) 32 (10.6) 67 (11.1)
Medical histor y, n (%)
Congestive heart failure 231(76.2) 231(76.2) 462 (76.2)
Hypertension 300 (99.0) 299 (98.7) 599 (98.8)
Diabetes 112 (37.0) 130 (42.9) 242 (39.9)
Ischemic/embolic stroke 30 (9.9) 24 (7.9) 54 (8.9)
BMI,body mass index; CHADS2,stroke risk stratication scheme for patients with atrial brillation (congestive heart failure,hypertension, age,diabetes,
previous stroke); CrCL, creatinine clearance; mITT, modied intent-to-treat; SD, standard deviation.
daily, as compared with patients receiving 60 mg once
daily (Table 2). The average edoxaban concentration at
steady state was 74.8 ng/mL in the 60-mg group and
93.2 ng/mL in the 75-mg group (Table 2).
Anti-FXa
The mean predose concentrations of anti-FXa in pa-
tients in the PD analysis set during days 30, 90, and
360 of the on-treatment period ranged from 23.1 to
28.0 ng/mL in the edoxaban 60-mg once-daily arm
and 33.4 to 35.9 ng/mL in the edoxaban 75-mg once-
daily arm. Anti-FXa levels for edoxaban 60 mg once
daily and 75 mg once daily at days 30, 90, and 360
are provided in Table 3. Figure 2 illustrates the linear
correlation between anti-FXa activity and edoxaban
concentration.
A post hoc analysis was also performed to exclude
the patients who had measurable anti-FXa at baseline
(likely due to concomitant heparin use). With this exclu-
sion, the change in anti-FXa levels also remained con-
sistent with the increase in dose.
Adjudicated Efcacy Outcomes
In the mITT population during the on-treatment pe-
riod, the incidence of the composite end point of stroke,
TIA, and SEEs was 0.7% (2/303) in the edoxaban
60-mg once-daily arm vs 1.0% (3/303) in the
edoxaban 75-mg arm (odds ratio, 1.51; 95%CI, 0.2-
18.1; P=1.000; Table 4). All events were stroke events;
Yin et al 5
Ta b l e 2 . Population Pharmacokinetic Parameters Estimates for Edoxaban at Steady State by Dose (Pharmacokinetic Analysis Set)
Edoxaban
60 mg Once
Daily (n =298)
Edoxaban
75 mg Once Daily
(n =297)
Cav (ng/mL)
Mean (SD) 74.8 (13.3) 93.2 (16.2)
Median (min-max) 74.5 (44.5-121) 92.4 (55.5-146)
Geometric mean/CV (%) 73.7/17.8 91.8/17.8
Ratio of means edoxaban
75/60 mg (95%CI)
1.25 (1.2-1.3)
Pvalue <.0001
Cmax,ng/mL
Mean (SD) 214(51.1) 269 (62.4)
Median (min-max) 211 (124-429) 261(144-496)
Geometric mean/CV (%) 209/23.7 262/23.2
Ratio of means edoxaban
75/60 mg (95%CI)
1.25 (1.2-1.3)
Pvalue <.0001
Cmin,ng/mL
Mean (SD) 18.2 (5.2) 22.5 (6.5)
Median (min-max) 17.8 (4.8-33.9) 22.1(8.7-42.4)
Geometric mean/CV (%) 17.4/30.6 21.6/30.5
Ratio of means edoxaban
75/60 mg (95%CI)
1.24 (1.2-1.3)
Pvalue <.0001
Cav, average plasma concentration of edoxaban at steady state; Cmax, maximum (peak) concentration of drug in blood plasma (applied to extravascular
drug administration); Cmin, minimum obser ved (or could infer lowest effective) concentration of edoxaban in blood plasma; CV, coefcient of variation;
min, minimum; max, maximum; SD,standard deviation.
there were no reported TIA or SEE events. In the
edoxaban 60-mg once-daily group, two patients expe-
rienced an ischemic stroke; in the 75-mg once-daily
group, 1 patient experienced an ischemic stroke and 2
experienced a hemorrhagic stroke (1 fatal). No other
patients in the mITT population experienced an event
during the overall study period. The annual event rate
of the composite end point was <1% during the study.
Adjudicated Safety Outcomes
Clinically relevant bleeding (major and/or CRNM
bleeding) during the on-treatment period occurred in
21 patients (3.5%) overall, with 11 patients (3.6%) in
the edoxaban 60-mg once-daily arm and 10 (3.3%) in
the edoxaban 75-mg once-daily arm (odds ratio, 0.9;
95%CI, 0.3-2.4; P=1.000). In the edoxaban 60-mg
once-daily arm, two patients (0.7%) experienced a ma-
jor bleeding event (1 event of intraocular bleeding and
1 intramuscular). There were no fatal bleeding events
in the edoxaban 60-mg once-daily arm. Nine patients
(3.0%) experienced a CRNM bleeding event in the
edoxaban 60-mg once-daily arm. In the edoxaban 75-
mg once-daily group, 3 patients (1.0%) experienced a
major bleeding event (2 experienced intracranial bleeds
[1 fatal], and 1 experienced an upper gastrointesti-
nal bleed). Seven patients (2.3%) experienced CRNM
bleeding in the edoxaban 75-mg once-daily arm. A sum-
mary of safety data related to bleeding is presented in
Table 4. No patient in either treatment group had more
than one conrmed on-treatment major bleeding event.
The PK data of edoxaban was examined for patients
with adjudicated and conrmed stroke or bleeding out-
come events, and no consistent relationship between
exposure and outcome events was observed (Table 5).
The exposures in patients with outcome events were
within the expected range (between the 5th and 95th
percentiles) and were not different from the exposure
range observed in all patients.
Treatment-Emergent AEs
Treatment-emergent AEs (TEAEs) occurred in 244 pa-
tients (40.3%) during the on-treatment period. The
most common TEAE was AF, which was reported by
11 patients (3.6%) in the 60-mg once-daily group and
14 (4.6%) in the 75-mg once-daily group. During the
overall study period, there were seven reported deaths:
2 patients receiving edoxaban 60 mg once daily and 5
patients receiving 75 mg once daily. Five of the deaths
were adjudicated as due to CV disease and not associ-
ated with a stroke or bleeding event within 30 days of
death; 1 death was due to urosepsis and adjudicated as
unrelated to the study medication. One death (edoxa-
6Clinical Pharmacology in Drug Development 2021, 0(0)
Ta b l e 3 . Anti-FXa (ng/mL) Measures at Days 30, 60, and 360 in Patients Receiving Edoxaban 60 mg Once Daily or Edoxaban 75 mg
Once Daily
Edoxaban 60 mg Once Daily (n =292) Edoxaban 75 mg Once Daily (n =292)
Before Dosing
1-2 h After
Dosing
4-8 h After
Dosing Before Dosing
1-2hAfter
Dosing
4-8 h After
Dosing
Day 30
N 284 280 280 284 291292
Mean (SD) 28 (58) 201(109) 161(63) 33 (58) 233 (122) 191(73)
Median
(min-max)
0 (0-400) 205 (0-400) 145 (27-400) 22 (0-397) 251(0-400) 181(0-400)
Day 90
N281281283 273 280 277
Mean (SD) 23 (47) 180 (107) 157 (67) 33 (59) 229 (120) 184 (79)
Median
(min-max)
0 (0-375) 173 (0-400) 144 (0-363) 22 (0-386) 234 (0-400) 174 (0-400)
Day 360
N 276 277 279 269 269 267
Mean (SD) 26 (55) 181(111)147 (77) 356 (59) 215(126) 184 (95)
Median
(min-max)
0 (0-399) 166 (0-400) 139 (0-400) 23 (0-387) 215 (0-400) 177 (0-400)
FXa, factor Xa; min-minimum; max, maximum; SD, standard deviation.
Figure 2. Scatterplot of edoxaban concentration versus anti-FXa in the PD analysis set. Anti-FXa values greater than the upper limit
of quantication (400 ng/mL) were reported as 400 ng/mL, and anti-FXa values less than the lower limit of quantication (20 ng/mL)
were reported as 0 ng/mL. FXa indicates factor Xa; PD, pharmacodynamics.
ban 75 mg once daily) was due to hemorrhagic stroke
(Table 4). No other TEAE occurred in >3% of patients
in either arm of the study. A summary of TEAEs is pre-
sented in Table S3.
Discussion
This study was conducted to determine if a daily dose
of edoxaban >60 mg would increase exposure among
patients with CrCL >100 mL/min. Over a period of
12 months, 303 patients received edoxaban 60 mg once
daily, and 304 received edoxaban 75 mg once daily.
On day 30, 1 to 2 hours after dosing, the edoxaban
concentration was 232 ng/mL in patients receiving the
60-mg dose and 281 ng/mL in patients receiving the
75-mg dose. As expected, given the linear edoxaban
dose proportionality, the edoxaban dose of 75 mg
once daily provided an ≈25% increase in exposure
Yin et al 7
Ta b l e 4 . Adjudicated Clinical Outcome Events (on Treatment) by Dose
Edoxaban
60 mg Once Daily
(n =303)
Edoxaban
75 mg Once Daily
(n =303) Overall (N =606)
Stroke, TIA, or SEE, n (%) – mITT 2 (0.7) 3 (1.0) 5 (0.8)
Ischemic stroke 2 13
Hemorrhagic stroke 0 2a2
TIA or SEE 0 0 0
Patient exposure years 307 303 610
Annualized event rate, % 0.7 1.0 0.9
95% exact CI for annualized event rate, % (0.1-2.4) (0.2-2.9) (0.3-1.9)
Odds ratio (95% exact CI): 75 mg vs 60 mg 1.51(0.17-18.1)1.00
Pvalue
Major or CRNM bleeding, n (%) – SAS 11 (3.6) 10 (3.3) 21(3.5)
Patient exposure years 292 287 579
Annualized event rate, % 3.8 3.5 3.6
95% exact CI for annualized event rate, % (1.9-6.8) (1.7-6.4) (2.2-5.5)
Odds ratio (95% exact CI): 75 mg vs 60 mg 0.91(0.34-2.39)1.00
Pvalue
Major bleeding, n (%) – SAS 2 (0.7) 3 (1.0) 5 (0.8)
Intracranial 0 2 (0.7)a2 (0.3)
Upper gastrointestinal 0 1(0.3) 1(0.2)
Patient exposure years 293 289 582
Annualized event rate, % 0.7 1.0 0.9
95% exact CI for annualized event rate, % (0.1-2.5) (0.2-3.0) (0.3-2.0)
Odds ratio (95% exact CI): 75 mg vs 60 mg 1.51(0.17-18.1)1.00
Pvalue
Net clinical end point,bn(%)–mITT 5(1.7) 8 (2.6) 13(2.1)
Patient exposure years 293 288 581
Annualized event rate, % 1.7 2.8 2.2
95% exact CI for annualized event rate, % (0.6-4.0) (1.2-5.5) (1.2-3.8)
Odds ratio (95% exact CI): 75 mg vs 60 mg 1.62 (0.46-6.35)
Pvalue .577
CRNM, clinically relevant nonmajor ; MI, myocardial infarction; mITT, modied intent-to-treat; SAS, safety analysis set; SEE, systemic embolic event; TIA,
transient ischemic attack.
aOne fatal.
bComposite of stroke, TIA, SEE, MI, cardiovascular death, and major bleeding.
compared with the edoxaban 60-mg once-daily dose.
This 25% increase was also accurately depicted in the
pop-PK model estimation of steady-state edoxaban
concentration. There was also an increase in anti-FXa
concentration between the 60- and 75-mg doses that
correlated well with edoxaban concentration.
In ENGAGE AF-TIMI 48, patients with
CrCL >95 mL/min showed a trend toward decreased
efcacy relative to warfarin and had lower edoxaban
trough concentrations relative to patients with lower
CrCL.6Of note, the demographics of patients with
high CrCL (>95 mL/min) in ENGAGE AF-TIMI 48
were similar to the patients enrolled in this study (Table
S3).6Although the current study was not designed to
compare clinical events between the 2 treatment arms
with sufcient power, the total number of patients
with clinical outcome events (stroke or bleeding) was
low overall and similar between the 2 treatment arms.
The observed increase in exposure with edoxaban
75 mg compared with 60 mg was not associated with a
decrease in the risk of overall stroke.
In the current study, AF patients with high renal
clearance receiving edoxaban 75 mg once daily (vs edox-
aban 60 mg once daily) demonstrated dose proportional
increases in edoxaban and anti-FXa concentrations.
Despite the increase in exposure, there was no apparent
additional clinical benet of the higher edoxaban dose,
as the rates of overall stroke were similar between treat-
ment arms. Therefore, the results of this study continue
to support that edoxaban 60 mg once daily provides ap-
propriate stroke prevention for patients with AF with
high renal clearance (CrCL >100 mL/min).
The current study is not without limitations. As
noted previously, this study was not designed to
8Clinical Pharmacology in Drug Development 2021, 0(0)
Ta b l e 5 . Cav,C
max,and C
min for Edoxaban at Steady State in Patients With Adjudicated Stroke or Bleeding Events (Safety Analysis
Set)
ID Dose (mg) Event Cav ,ng/mL C
max,ng/mL C
min ng/mL
Patient 160 Intramuscular
bleeding
65.9 169 17.8
Patient 2 60 Ischemic stroke 66.7 186 16.1
Patient 3 60 Ischemic stroke 68.9 198 14.9
Patient 4 60 Eye (intraocular)
bleeding
87.8 237 23.5
Patient 5 75 GI bleeding 102 263 29.2
Patient 6 75 Ischemic stroke 93.3 368 11.2
Patient 7 75 Hemorrhagic
stroke/ICH
72.3 21515.1
Patient 8 75 Hemorrhagic
stroke/ICH
104 266 29.6
All patients 60 Mean (n =298) 74.8 21418.2
All patients 60 Median (n =298) 74.5 211 17.8
All patients 75 Mean (n =297) 93.2 269 22.5
All patients 75 Median (n =297) 92.4 26122.1
Cav, average plasma concentration of edoxaban at steady state; Cmax , maximum concentration in plasma; Cmin , minimum concentration in plasma; GI,
gastrointestinal; ICH, intracranial hemorrhage.
compare clinical events between the 2 treatment arms
with sufcient power, given the low incidence of stroke
and bleeding events in this subpopulation of patients
with AF treated with FXa inhibitors. Accordingly,
analysis of stroke, embolism, and other events served
to support the exposure analyses. Additionally, renal
function may have been more adequately described by
formulas other than the Cockcroft-Gault formula, al-
though this is a commonly used and accepted method.15
Other methods for estimation of renal clearance, such
as the Chronic Kidney Disease Epidemiology Collab-
oration and the Modication of Diet in Renal Disease
equations that consider a number of demographic
factors in various congurations, may have provided
further insight into renal function.16
Conclusions
This study conrmed that edoxaban exposure was
≈25% higher in patients with AF with high renal clear-
ance (CrCL >100 mL/min) who received edoxaban
75 mg once daily compared with patients who received
edoxaban 60 mg once daily. The increases in anti-FXa
levels were also in line with the increase in dose. The risk
of overall stroke and major/clinically relevant bleed-
ing was similar in both treatment arms. Additionally,
the exposures in patients with outcome events were
within the expected range (between the 5th and 95th
percentiles) and were not different from the exposure
range observed in all patients. The results of this study
continue to support that edoxaban 60 mg once daily
provides appropriate stroke prevention for patients with
AF with high renal clearance (CrCL >100 mL/min).
Acknowledgments
This study was sponsored by Daiichi Sankyo. Writing and ed-
itorial support was provided by Margaret Van Horn, PhD,
and Lauren Hanlon, PhD, of AlphaBioCom, LLC and was
funded by Daiichi Sankyo.
Conicts of Interest
All authors are/were employees of Daiichi Sankyo, Inc. at the
time of manuscript development and creation.
Funding
This study was funded by Daiichi Sankyo.
Author Contribution
All authors contributed to the study concept and design. OY,
TK, AD, MK, MS, and MG performed material prepara-
tion, data collection, and analysis. OY, TK, AD, HL, and MG
contributed to writing the manuscript, and all authors com-
mented on previous versions of the manuscript. All authors
read and approved the nal manuscript.
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