Special Populations

The Journal of Clinical Pharmacology

Pharmacokinetics, Pharmacodynamics, 2016, 56(5) 628–636
© 2015, The American College of
and Safety of Apixaban in Subjects With Clinical Pharmacology
DOI: 10.1002/jcph.628
End-Stage Renal Disease on Hemodialysis

Xiaoli Wang, PhD1, Giridhar Tirucherai, PhD1, Thomas C. Marbury, MD2,

Jessie Wang, MD, PhD1, Ming Chang, PhD1, Donglu Zhang, PhD1, Yan Song, PhD1,
Janice Pursley, BS1, Rebecca A. Boyd, PhD3, and Charles Frost, PharmD1

Abstract
An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects
with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was
administered once to healthy subjects and twice to subjects with ESRD, separated by 7 days: 2 hours before (on hemodialysis) and immediately after a
4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of
clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with
healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in
subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline
in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban
concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in
apixaban AUC and no increase in Cmax, and hemodialysis had a limited impact on apixaban clearance.

Keywords
apixaban, pharmacokinetics, pharmacodynamics, end-stage renal disease, hemodialysis

Apixaban is an oral, selective, direct reversible inhibitor of
the coagulation factor Xa (FXa), approved in a number of
countries for thromboprophylaxis in patients who have
undergone elective hip or knee replacement surgery,1–3 for
reducing the risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation,4,5 and for the
treatment of deep vein thrombosis (DVT) and pulmonary
embolism (PE), and reduction in the risk of recurrent DVT
and PE following initial therapy.6,7 Apixaban is eliminated
by multiple pathways, including metabolism, excretion
into the intestine, and renal elimination.8
An evaluation of the effect of mild, moderate, and
severe renal impairment on apixaban pharmacokinetics
and pharmacodynamics demonstrated that apixaban
exposure increases with decreasing renal function, but
that the increase in exposure is modest.9 Apixaban area
under the plasma concentration-versus-time curve (AUC)
is estimated to be 44% higher in subjects with severe renal
impairment (creatinine clearance [CLcr], 15 mL/min)
than in subjects with normal renal function following
administration of a single dose, with no increase in
maximum observed plasma concentration (Cmax).
The primary objective of this study was to assess the
pharmacokinetics of a single oral dose of apixaban (5 mg) in
subjects with end-stage renal disease (ESRD) maintained
on chronic stable hemodialysis compared with subjects with
normal renal function. Secondary objectives were to assess:
(1) the effect of hemodialysis on the pharmacokinetics of
apixaban in subjects with ESRD; (2) the effect of apixaban
on the international normalized ratio (INR), prothrombin
time (PT), activated partial thromboplastin time (aPTT),
and anti-FXa activity in ESRD and healthy subjects; and
(3) the safety and tolerability of apixaban in ESRD and
healthy subjects.
Methods
The protocol was approved by the Independent Investi-
gational Review Board (Plantation, Florida) prior to study
1
At time of research, Bristol-Myers Squibb, Princeton, NJ, USA
2
Orlando Clinical Research Center, Orlando, FL, USA
3
Pfizer Inc, Groton, CT, USA
Submitted for publication 29 May 2015; accepted 26 August 2015.
Corresponding Author:
Charles Frost, PharmD, Bristol-Myers Squibb Company, Discovery
Medicine and Clinical Pharmacology, Mail Stop E12-16, Route 206 &
Province Line Road, Princeton, NJ 08543
Email: charles.frost@bms.com
Wang et al
initiation and complied with all local regulations, the
Declaration of Helsinki, and the International Conference
on Harmonisation guidelines on Good Clinical Practice.
Written informed consent was obtained from each subject
prior to enrollment in the study.
Study Design
This was an open-label, parallel-group, single-dose study
in 16 subjects conducted at the Orlando Clinical Research
Center, Orlando, Florida. Subjects were enrolled into 1 of
2 groups (n ¼ 8 per group) according to their degree of
renal function (healthy subjects or subjects with ESRD
on hemodialysis). Healthy subjects were individually
matched to subjects with ESRD maintained on hemodial-
ysis with regard to age (5 years), weight (total body
weight for healthy subjects was to be within 20% of body
weight obtained after dialysis for subjects with ESRD),
and sex.
Male and female subjects, aged 18 to 65 years with
either normal renal function (as determined by calculated
CLcr > 80 mL/min using the method of Cockcroft and
Gault10) or ESRD and on chronic and stable hemodialysis,
were recruited. Subjects with normal renal function were
excluded if they had a clinically significant deviation
from normal in physical examination, vital signs,
electrocardiogram (ECG), or clinical laboratory tests.
Subjects with ESRD were excluded if they exhibited
clinical or laboratory abnormalities beyond those consis-
tent with their degree of renal dysfunction.
Other key exclusion criteria included any significant
history of uncontrolled or unstable cardiovascular,
respiratory, hepatic, gastrointestinal, endocrine, hemato-
poietic, psychiatric, and/or neurological disease in the
6 months prior to study participation; history or evidence of
abnormal bleeding or coagulation disorder; intracranial
hemorrhage, abnormal bleeding, or coagulation disorder in
a first-degree relative; history of gastrointestinal-related
disorders that would impact absorption of the study drug;
and use of concomitant medications likely to impair
hemostasis or alter apixaban pharmacokinetics or pharma-
codynamics. Subjects were required to have liver function
test results  2  the upper limit of normal (ULN); INR,
PT, and aPTT values < ULN; hemoglobin < 10 g/dL;
hematocrit < 30%, and a platelet count < 100 000/mm3.
All women were required to have a negative serum
pregnancy test within 24 hours prior to study medication
administration. All women of childbearing potential who
were nursing, pregnant, or not using an acceptable method
of contraception for at least 1 month before dosing were
excluded from the study.
Healthy subjects were admitted to the clinical facility
on the day prior to dosing, administered a single oral
dose of apixaban 5 mg on day 1, and discharged from the
clinical facility on day 4, following collection of the final
pharmacokinetic and pharmacodynamic blood samples
629
and completion of the safety evaluations. The subjects
with ESRD were admitted to the clinical facility for a
period of 15 days, during which time they followed a
thrice-weekly dialysis schedule and received 2 single
oral 5-mg doses of apixaban, separated by a washout of at
least 7 days. On day 1 of period 1, a 5-mg oral dose
was administered, followed 2 hours later by a 4-hour
hemodialysis session (on hemodialysis period). On day 1
of period 2, subjects were administered a second 5-mg
oral dose of apixaban immediately following a 4-hour
hemodialysis session, with the next session not performed
until completion of the 72-hour time point sample (off
hemodialysis period). All hemodialysis sessions were
performed heparin-free (using saline flushes only). The
subjects with ESRD were discharged from the clinical
facility on day 8 of period 2, following completion of their
last hemodialysis session and safety evaluations. All
subjects were closely monitored for adverse events (AEs)
throughout the study.
Hemodialysis Methodology
Standardized hemodialysis sessions were carried out for
subjects with ESRD using an Optiflux F180NR hollow
fiber dialyzer (Fresenius Medical Care, Waltham, Massa-
chusetts), with an inner diameter of 200 mm and a surface
area of 1.8 m2. The duration of the hemodialysis treatments
was 4 hours. Dialysate flow rate was 500 mL/min, and
blood flow rate ranged from 350 to 500 mL/min.
Pharmacokinetic Sampling and Analyses
Blood samples for pharmacokinetic analyses were col-
lected in tubes containing 3.2% sodium citrate predose and
0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 60, and
72 hours postdose in all subjects. The 72-hour blood sample
was collected prior to the start of the next hemodialysis
session in subjects with ESRD. For the subjects with ESRD
in period 1, 2 blood samples were collected at the 2-, 2.5-,
3-, 4-, and 6-hour times: 1 sample collected prior to entering
the dialyzer and the second sample collected after exiting
the dialyzer. Immediately after collection, each blood
sample was gently inverted for complete mixing with the
anticoagulant and centrifuged to separate the plasma,
which was stored frozen at 20°C until analyzed. Urine
samples for pharmacokinetic analysis were collected
predose and over the 0- to 12-, 12- to 24-, 24- to 48-,
and 48- to 72-hour postdose intervals in healthy subjects
and in subjects with ESRD, provided they were not
functionally anuric. After thorough mixing and measure-
ment of volume, an aliquot was obtained from each
collection and stored frozen at 20°C until analyzed. A
blood sample for assessment of serum protein binding by
equilibrium dialysis was collected 4 hours postdose in
healthy subjects and during period 1 in subjects with
ESRD. In addition, a post hoc assessment of apixaban
protein binding during period 2 in subjects with ESRD was
630
performed using residual plasma from the 4-hour postdose
pharmacokinetic plasma sample. All protein-binding
samples were stored frozen at 20°C until analyzed. In
subjects with ESRD, dialysate samples were collected at
hourly intervals during the dialysis session (from 2 to
6 hours after the apixaban dose), in addition to a sample
collected before starting dialysis and a sample collected
after completion of dialysis on day 1 of period 1. For each
collection, the volume was recorded and an aliquot stored
frozen at 70°C until analyzed.
Apixaban in plasma, urine, dialysate, and serum:buffer
or plasma:buffer (from ex vivo equilibrium dialysis) was
assayed using a validated liquid chromatography with
tandem mass spectrometry (LC-MS/MS) method11 at
Intertek Pharmaceutical Services (El Dorado Hills,
California). Equilibrium dialysis samples were assayed
in triplicate. The lower limit of quantification (LLOQ)
was 1 ng/mL in plasma, urine, dialysate, and equilibrium
dialysis buffer samples. The between-run and within-run
variability for measurement of apixaban across matrices,
expressed as percent coefficient of variation (%CV), was
6.41% and 6.50%, respectively. Deviations from the
nominal concentration were no more than 8.49%. All
analyses were carried out during the period of known
analyte stability.
The following pharmacokinetic parameters were
derived for apixaban in healthy subjects and subjects
with ESRD (both periods) by standard noncompartmental
methods using Kinetica (version 5.0; Thermo Scientific,
Waltham, Massachusetts): Cmax, AUC from time zero
to the time of the last quantifiable concentration
(AUC0–T), AUC extended to infinity (AUCinf), time to
maximum concentration (Tmax), elimination half-life
(T1/2), apparent oral clearance (CL/F), and renal clearance
(CLR). Concentrations from samples entering the dialyzer
were used in the calculation of AUC0–T and AUCinf for
subjects with ESRD in period 1. In addition, the
following parameters were derived for apixaban in
subjects with ESRD in period 1: AUC from 2 to 6 hours
postdose determined from blood samples entering the
dialyzer (AUC2–6, entering) and exiting the dialyzer
(AUC2–6, exiting), the amount excreted in dialysate
(DR2–6), hemodialysis clearance (CLD; calculated as
DR2–6 divided by AUC2–6, entering)12 and hemodialysis
extraction ratio (fraction of apixaban entering the
dialyzer that was removed during the 4-hour
session), expressed as a percentage ([AUC2–6, entering 
AUC2–6, exiting]/AUC2–6, entering  100). The fraction of
apixaban unbound in serum or plasma (Fu) was
determined for each aliquot that underwent equilibrium
dialysis (3 aliquots per subject sample) by dividing the
buffer concentration by the serum or plasma concentra-
tion, and expressed as a percentage. The pharmacokinetic
parameters (Cmax and AUC) for total apixaban were
multiplied by Fu to obtain the unbound pharmacokinetic
The Journal of Clinical Pharmacology / Vol 56 No 5 2016
parameters, and the unbound CL/F was obtained by
dividing total CL/F by Fu.
Pharmacodynamic Sampling and Analyses
Blood samples for pharmacodynamic analyses were
collected in tubes containing 3.2% sodium citrate predose
and 0.5, 1.5, 3, 6, 12, 24, 48, and 72 hours postdose in all
subjects, with additional samples collected at 2, 2.5, and
4 hours in subjects with ESRD. The 72-hour blood sample
was collected prior to the start of the next hemodialysis
session in subjects with ESRD. Measurements of PT,
INR, and aPTT were performed at Quintiles Laboratories
(Marietta, Georgia) using validated methods on an ACL
TOP coagulation analyzer. The PT/INR reagent used was
HemosIL PT-Fibrinogen (international sensitivity index,
1.8). The aPTT reagent was HemosIL SynthASil and
0.020 M calcium chloride (Instrumentation Laboratory
Company, Bedford, Massachusetts). The normal ranges
were: 10–13 seconds for PT, 0.5–1.5 for INR, and 20.6–
39.9 seconds for aPTT. Anti-FXa activity was measured
with a validated method at Esoterix Coagulation
Laboratory (Englewood, Colorado) using a Diagnostica
Stago Rotachrom Heparin assay on a STA-Compact
analyzer.13 The results of this chromogenic assay were
reported in low-molecular-weight heparin activity units
(assay reportable range, 0.1–19.7 IU/mL).
Safety and Tolerability Assessments
Safety assessments were based on AE reports and the
results of vital sign measurements, ECGs, physical
examinations, and clinical laboratory tests. All AEs
were classified, recorded, and reported according to their
degree of severity. Subjects were only discharged from
the study when the investigator had determined that all
AEs had completely resolved or were not of clinical
significance.
Statistical Methods
Summary statistics are provided for each apixaban
pharmacokinetic parameter (ie, in plasma, dialysate,
and urine) by renal status group and study period (subjects
with ESRD only), as appropriate. Geometric means
and %CV are presented for Cmax, AUC, and clearance
parameters. Medians, minima, and maxima are presented
for Tmax. Means and standard deviations are provided for
T1/2, DR2–6, and hemodialysis extraction ratio. Percent Fu
was tabulated by renal status group and study period
(subjects with ESRD only), and means and standard
deviations are provided.
To estimate the effect of ESRD on the pharmacoki-
netics of apixaban (subjects with ESRD off hemodialysis
in period 2 vs healthy subjects) or the exposure in subjects
with ESRD on hemodialysis (period 1) versus that in
healthy subjects, analysis of variance was performed on
the log(Cmax) and log(AUCinf) of apixaban, including
Wang et al 631

group as a fixed effect. Point estimates and 90% Table 1. Subject Demographics and Baseline Characteristics
confidence intervals (CIs) for differences on the log scale Healthy Subjects Subjects With ESRD
were exponentiated to obtain estimates for ratios of
geometric means and 90%CIs on the original scale. Characteristics n¼8 n¼8
To estimate the effect of hemodialysis on the Age (y)
pharmacokinetics of apixaban in subjects with ESRD Mean (SD) 47.0 (7.7) 46.9 (7.9)
(on hemodialysis in period 1 vs off hemodialysis in Range 34–59 36–63
period 2), a general linear mixed-effects model analysis Sex, n (%)
was performed on the log(Cmax) and log(AUCinf) of Male 6 (75.0) 6 (75.0)
apixaban. Factors in the model were period as a fixed effect Race, n (%)
White 6 (75.0) 1(12.5)
and measurements within subjects as repeated measures.
Black/African American 1 (12.5) 7 (87.5)
Point estimates and 90%CIs for differences on the log scale American Indian/Alaska Native 1 (12.5) 0
were exponentiated to obtain estimates for ratios of Weight (kg)
geometric means and 90%CIs on the original scale. Mean (SD) 87.4 (18.4) 92.5 (21.2)
All available pharmacodynamic data from the subjects Range 66.3–115 62.2–126
for whom pharmacodynamic measurements were avail- Dry body weighta (kg)
able at baseline and at least 1 other time were included in Mean (SD) N/A 90.7 (21.3)
Range 60.7–124.9
the pharmacodynamic data set. Summary statistics for
Body mass index (kg/m2)
INR, PT, aPTT, and anti-FXa activity were tabulated by Mean (SD) 29.7 (3.9) 29.7 (7.4)
renal status group, study period (subjects with ESRD Range 24.8–35.0 21.9–41.8
only), and time. In addition, maximum postdose value and CLcr at screening (mL/min)
percent change from baseline are summarized for the Mean (SD) 125 (25.4) N/A
coagulation measures (INR, PT, and aPTT). Baseline was Range 86–150
established from the predose results on day 1 for healthy
subjects and on day 1 of each period for subjects with CLcr, creatinine clearance; ESRD, end-stage renal disease; N/A, not
applicable; SD, standard deviation.
ESRD. Plots of mean profiles over time for INR, PT, a
Dry body weight is measured after hemodialysis.
aPTT, and anti-FXa activity by group and study period
and a scatterplot of anti-FXa activity versus apixaban
concentration were generated. Apixaban concentration and then declined in a multiphasic manner in both
values and anti-FXa activity values < LLOQ were set to 0 healthy subjects and subjects with ESRD, on or off
for predose samples and to half LLOQ for postdose hemodialysis (Figure 1). The mean T1/2 value in
samples in the scatterplot. subjects with ESRD in periods 1 and 2 was approximately
All recorded AEs are listed and tabulated by system 13 hours, and the mean T1/2 in healthy subjects was 20 hours.
organ class, preferred term, and treatment. Vital signs and Compared with healthy subjects, the geometric means of
clinical laboratory test results are listed and summarized apixaban Cmax and AUCinf were 10% lower and 36%
by treatment. Any significant physical examination higher, respectively, in subjects with ESRD when apixaban
findings, clinical laboratory results, and ECG abnormali- was administered immediately after completion of
ties are listed. hemodialysis (Table 2). Hemodialysis reduced the geo-
metric means of apixaban Cmax and AUCinf by 13% and
14%, respectively, in subjects with ESRD, when started
Results 2 hours after apixaban administration (Table 2). Dialysate
Subject Disposition clearance in subjects with ESRD (17.7 mL/min) was higher
Eight healthy subjects (mean CLcr, 125 mL/min) and 8 than CLR in healthy subjects (11.3 mL/min). The recovery
with ESRD who were maintained on hemodialysis (6 men of apixaban in the dialysate was approximately 0.33 mg,
and 2 women in each group) were treated and completed representing 6.7% of the apixaban dose. The calculated
the study. Subject demographics and baseline character- hemodialysis extraction ratio was 1.1%. Three of
istics are shown in Table 1. The 2 groups of subjects were 8 subjects with ESRD were functionally anuric. In the
well matched for age and body size. The majority of 5 subjects with ESRD from whom urine was collected,
subjects (n ¼ 7) in the ESRD group were black/African the volume of urine ranged from 9 to 490 mL/day.
American, and the majority (n ¼ 6) of the subjects in the Apixaban CLR was very limited in subjects with ESRD
healthy group were white. (<1 mL/min) compared with healthy subjects.
Apixaban protein binding was generally comparable
Pharmacokinetics between healthy subjects (mean [standard deviation]
After a single oral dose of 5 mg apixaban, plasma Fu, 6.8% [0.71%]) and subjects with ESRD (Fu,
concentration peaked approximately 2 hours postdose 5.9% [0.97%] and 8.5% [1.2%] in periods 1 and 2,
632
Figure 1. Mean apixaban plasma concentration-versus-time profiles
following a single oral 5-mg dose in healthy subjects and subjects with
ESRD who were maintained on hemodialysis. (A) Linear scale. (B) Log
scale. ESRD, end-stage renal disease. For subjects with ESRD,
hemodialysis was started 2 hours after apixaban administration in
period 1 (on dialysis), and apixaban was administered immediately
after hemodialysis in period 2 (off dialysis). Error bars show þ1 standard
deviation.
respectively). Thus, unbound apixaban pharmacokinetic
parameters followed trends similar to those based on total
concentrations (data not shown).
Pharmacodynamics
Mean apixaban pharmacodynamic (INR, PT, aPTT, and
anti-FXa activity) profiles over time are provided in
Figure 2, and summary statistics for the maximum change
in measures of coagulation are shown in Table 3. Only
small changes in INR, PT, and aPTT were observed
following administration of apixaban, and the maximum
changes were generally not greater in subjects with ESRD
than in healthy subjects. The anti-FXa activity–versus-
time profile closely tracked that for apixaban plasma
concentration-versus-time, with peak anti-FXa activity of
1.47 IU/mL in healthy subjects and 1.03 and 1.29 IU/mL
in subjects with ESRD in periods 1 and 2, respectively. A
direct linear relationship between anti-FXa activity values
and apixaban plasma concentrations was observed for
both healthy subjects and subjects with ESRD, with a
slightly lower slope for subjects with ESRD (Figure 3).
The Journal of Clinical Pharmacology / Vol 56 No 5 2016
Safety and Tolerability
No deaths, serious AEs, discontinuations due to AEs, or
bleeding-related AEs occurred during the study. The most
frequently reported AE was headache, which occurred in
2 subjects with ESRD. No AEs were reported in healthy
subjects. One subject with ESRD experienced a severe
AE of procedural hypotension during hemodialysis on
day 4 (3 days following the apixaban dose), which was
considered by the investigator to be unrelated to the study
treatment. All other AEs were mild or moderate in
intensity and all AEs resolved prior to study completion.
There were no clinically significant changes in laboratory
tests, vital signs, ECGs, or physical examination results.
Discussion
This study was conducted to investigate the effect of
ESRD on apixaban pharmacokinetics and pharmacody-
namics and to assess the ability of hemodialysis to remove
apixaban from the systemic circulation. The approxi-
mately 36% higher total apixaban exposure in subjects
with ESRD administered apixaban following a hemodi-
alysis session compared with healthy subjects is reflective
of the reduced apixaban clearance in these subjects, as
other potential determinants of apixaban exposure (age,
sex, body size) were well matched between the 2 groups.
Although the proportion of white and black/African
American subjects was different in the 2 groups, this is
unlikely to have contributed to the difference in apixaban
exposure, as there is no evidence that the pharmacokinet-
ics of apixaban differ between these 2 racial groups.14
Given the negligible CLR in subjects with ESRD, other
pathways (ie, cytochrome P450 metabolism, biliary
excretion, and direct intestinal excretion) are responsible
for the elimination of apixaban in this population. Renal
clearance is estimated to represent approximately 27%
of the total clearance of apixaban in healthy subjects14
based on the results of 2 studies following intravenous
administration.15,16 The observed increase in apixaban
exposure in subjects with ESRD is consistent with this
estimate and suggests no impact of ESRD on apixaban
absorption or other pathways of elimination. Furthermore,
this result is consistent with the 44% increase in apixaban
exposure in subjects with severe renal impairment (CLcr,
15 mL/min) observed in a previous study.9 These results
suggest that apixaban can be used in patients with ESRD
maintained on hemodialysis without the need for dose
modification, unless they have nonvalvular atrial fibrilla-
tion and meet the criteria for a dose reduction from 5 to
2.5 mg twice daily (age  80 years and/or body weight
 60 kg in addition to their renal failure).
The mean apixaban T1/2 value of 13 hours in subjects
with ESRD was similar to values reported previously in
healthy subjects.17,18 The mean T1/2 value of 20 hours in
healthy subjects was somewhat longer. One healthy
Wang et al 633

Table 2. Summary of Apixaban Pharmacokinetic Parameters and Results of Statistical Analysis of Apixaban Cmax and AUCinf

Parameter

Cmax AUCinf CL/F CLR CLD

(ng/mL), (ng  h/mL), Tmax (h), (mL/min), (mL/min), (mL/min), Extraction
Group and geo mean geo mean median T1/2 (h) geo mean geo mean Fu (%), geo mean %DR, ratio (%),
Period (%CV) (%CV) (min, max) mean (SD) (%CV) (%CV) mean (SD) (%CV) mean (SD) mean (SD)

Healthy subjects 126 (29) 1265 (30) 2.0 (1.0, 4.0) 20.0 (14.45) 65.9 (33) 11.3 (44) 6.8 (0.71) N/A N/A N/A
(n ¼ 8)
Subjects with ESRD
(n ¼ 8a)
Period 1 98.9 (29) 1474 (44) 2.0 (1.0, 6.0) 12.5 (3.14) 56.6 (24) 0.02a (70) 5.9 (0.97) 17.7 (19) 6.7 (1.4) 1.1 (5.7)
Period 2 114 (31) 1717 (24) 2.0 (2.0, 6.0) 12.7 (3.40) 48.5 (22) 0.02a (80) 8.5 (1.2) N/A N/A N/A

Geometric Mean Ratio (90%CI) Estimated From the Statistical Analysis Models

Comparison Cmax (ng/mL) AUCinf (ng  h/mL)

Subjects with ESRD period 1 0.79 (0.62–1.01) 1.17 (0.88–1.54)

vs healthy subjects
Subjects with ESRD period 2 0.90 (0.70–1.17) 1.36 (1.07–1.73)
vs healthy subjects
Subjects with ESRD period 1 0.87 (0.72–1.05) 0.86 (0.71–1.04)
vs period 2

AUCinf, area under the plasma concentration versus time curve extended to infinity; CI, confidence interval; CLD, hemodialysis clearance; CLR, renal clearance;
CL/F, apparent oral clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; ESRD, end-stage renal disease; Fu, fraction (percent) unbound;
Geo, geometric; N/A, not applicable; period 1, hemodialysis started 2 hours after apixaban administration (on dialysis); period 2, apixaban administered
immediately after hemodialysis (off dialysis); SD, standard deviation; T1/2, elimination half-life; Tmax, time to maximum concentration; %DR, percentage
dialysate recovery.
a
n ¼ 5 for urine parameters.

subject had an apparent T1/2 value of 48.5 hours, which was
attributed to concentrations for the last 3 times being
near the LLOQ. The median T1/2 value in healthy subjects
was 15 hours, compared with median values of 12 and
14 hours in subjects with ESRD in periods 1 and 2,
respectively.
A 4-hour hemodialysis session was associated with a
decrease in apixaban exposure of 14% in subjects with
ESRD and a 17% increase in apparent oral clearance,
and removed 0.33 mg of apixaban. The calculated
hemodialysis extraction ratio was negligible, with the
exiting concentrations of apixaban slightly higher than
entering concentrations. This may have been caused by
water loss from plasma during hemodialysis (the total
fluid loss during dialysis was 6 L for all subjects), as
has previously been observed for olmesartan.19 Given
the limited removal of apixaban by a 4-hour hemodialy-
sis session in these subjects with ESRD, timing of a dose
relative to hemodialysis is not important, and hemodial-
ysis is unlikely to be useful for removing apixaban
from the systemic circulation in other situations (eg,
overdose).
In this study, apixaban protein binding in healthy
subjects and subjects with ESRD was generally similar to
that reported previously in healthy subjects and those
with hepatic impairment (Fu of 7% to 8%).20 Although
Fu appeared to be slightly higher (8.5% vs 5.9%) in
subjects with ESRD when apixaban was administered
immediately after hemodialysis than when apixaban was
administered 2 hours prior to hemodialysis, these results
should be interpreted with caution given the difference in
sample matrix (plasma vs serum) used for assessment of
protein binding in the 2 periods. The apparent difference
in Fu between these 2 periods had no evident impact on
anti-FXa activity.
The pharmacodynamic results demonstrated the lack
of sensitivity and variability of the measures of clotting
(INR, PT, and aPTT), similar to observations in previous
studies.17,18 Thus, it is not surprising that little difference
in response was observed between subjects with ESRD
and healthy subjects. There was a close linear relationship
between apixaban plasma concentration and anti-FXa
activity, as previously observed in healthy subjects,21,22
and the slope of the relationship was slightly lower in
subjects with ESRD. No apparent differences in this
relationship were observed in subjects with mild to severe
renal impairment compared with healthy subjects,9 and
thus the small difference observed in this study may
reflect expected variability for a comparison of results in
2 small groups of subjects.
634 The Journal of Clinical Pharmacology / Vol 56 No 5 2016

Figure 2. Changes in pharmacodynamic parameters over time. (A) Mean INR versus time. (B) Mean PT versus time. (C) Mean aPTT versus
time. (D) Mean anti-FXa activity versus time. aPTT, activated partial thromboplastin time; ESRD, end-stage renal disease; FXa, factor Xa;
INR, international normalized ratio; PT, prothrombin time. For subjects with ESRD, hemodialysis was started 2 hours after apixaban
administration in period 1 (on dialysis), and apixaban was administered immediately after hemodialysis in period 2 (off dialysis). Error bars
show 1 standard error.

It should be noted that the hemodialysis sessions were
performed heparin-free to ensure there would be no
interference with the pharmacodynamic measures for
apixaban. Thus, if heparin flushes are used in ESRD
patients on hemodialysis who are taking apixaban, results
of these assays may not accurately reflect the apixaban
response.
A single 5-mg oral dose of apixaban was safe and well
tolerated by healthy subjects and subjects with ESRD who
were maintained on hemodialysis. There were no serious
AEs, discontinuations due to AEs, or bleeding-related
AEs, and there were no clinically relevant findings from
the monitoring of vital signs, ECGs, or clinical laboratory
assessments.

Table 3. Summary of Apixaban Pharmacodynamic Parameters

Healthy Subjects Subjects With ESRD, Period 1 Subjects With ESRD, Period 2

INR Baseline (SD) 0.97 (0.09) 1.07 (0.13) 1.09 (0.15)

Maximum postdose value (SD) 1.24 (0.42) 1.25 (0.17) 1.28 (0.20)
Maximum percent change from baseline, % (SD) 31.5 (56.6) 16.6 (10.6) 16.8 (7.2)
PT Baseline, seconds (SD) 11.5 (1.2) 12.8 (1.5) 13.0 (1.8)
Maximum postdose value, seconds (SD) 14.8 (5.2) 14.9 (2.1) 15.3 (2.5)
Maximum percent change from baseline, % (SD) 32.4 (58.3) 16.9 (11.0) 17.4 (7.3)
aPTT Baseline, seconds (SD) 34.3 (4.8) 36.4 (6.0) 31.5 (6.7)
Maximum postdose value, seconds (SD) 40.6 (4.7) 38.7 (2.2) 38.0 (4.1)
Maximum percent change from baseline, % (SD) 19.9 (20.4) 7.0 (9.6) 23.0 (14.8)

aPTT, activated partial thromboplastin time; ESRD, end-stage renal disease; INR, international normalized ratio; period 1, hemodialysis started 2 hours after
apixaban administration (on dialysis); period 2, apixaban administered immediately after hemodialysis (off dialysis); PT, prothrombin time; SD, standard deviation.
Wang et al
Figure 3. Scatterplot of anti-FXa activity versus apixaban plasma
concentration. The slope (95%CI) of the regression line for healthy
subjects and subjects with ESRD was 0.0140 (0.0135–0.0145) and
0.0116 (0.0110–0.0121), respectively. CI, confidence interval; ESRD,
end-stage renal disease. For subjects with ESRD, hemodialysis was
started 2 hours after apixaban administration in period 1 (on dialysis),
and apixaban was administered immediately after hemodialysis in period
2 (off dialysis).
The pharmacokinetic and pharmacodynamic results of
this study suggest that apixaban can be used without dose
modification in patients with ESRD maintained on
hemodialysis. This conclusion is based on the modest
increase in apixaban exposure off hemodialysis and
the limited removal of apixaban during hemodialysis
observed in the ESRD subjects in this study. The dosing
guidance for patients with ESRD in the US prescribing
information14 is based on these data. No dose adjustment
is recommended in ESRD patients for any indication,
with the exception of certain patients with nonvalvular
atrial fibrillation. In patients with nonvalvular atrial
fibrillation with ESRD and at least 1 of the following
characteristics, age  80 years and body weight  60 kg,
it is recommended that the apixaban dose be reduced from
5 mg twice daily to 2.5 mg twice daily. It is important to
note that the efficacy and safety of apixaban in ESRD
patients on hemodialysis have not been studied; therefore,
the benefit–risk profile of apixaban is unknown in these
patients.
Declaration of Conflicting Interests
X.W., G.T., J.W., M.C., Y.S., J.P., and C.F. are employees of
Bristol-Myers Squibb, Princeton, New Jersey; D.Z. was an
employee of Bristol-Myers Squibb, Princeton, New Jersey, at
the time this research was conducted. R.A.B. is an employee of
Pfizer Inc., Groton, Connecticut; T.C.M. is an employee of
Orlando Clinical Research Center.
Funding
This study was funded by Bristol-Myers Squibb and Pfizer Inc.
Professional medical writing and editorial assistance was
provided by Claire Hall, PhD, and Andy Shepherd, PhD, at
Caudex, funded by Bristol-Myers Squibb and Pfizer Inc.
635
References
1. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P;
ADVANCE-2 investigators. Apixaban versus enoxaparin for
thromboprophylaxis after knee replacement (ADVANCE-2):
a randomised double-blind trial. Lancet. 2010;375(9717):
807815.
2. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ.
Apixaban or enoxaparin for thromboprophylaxis after knee
replacement. N Engl J Med. 2009;361(6):594604.
3. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM.
Apixaban versus enoxaparin for thromboprophylaxis after hip
replacement. N Engl J Med. 2010;363(26):24872498.
4. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with
atrial fibrillation. N Engl J Med. 2011;364(9):806–817.
5. Granger CB, Alexander JH, McMurray JJV, et al; ARISTOTLE
committees and investigators. Apixaban versus warfarin in patients
with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.
6. Agnelli G, Buller HR, Cohen, et al; AMPLIFY Investigators. Oral
apixaban for the treatment of acute venous thromboembolism.
N Engl J Med. 2013;369(9):799808.
7. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY-EXT
Investigators. Apixaban for extended treatment of venous throm-
boembolism. N Engl J Med. 2013;368(8):699708.
8. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and
pharmacokinetics after oral administration to humans. Drug Metab
Dispos. 2009;37(1):74–81.
9. Chang M, Yu Z, Byon W, et al. Effect of renal impairment on the
pharmacokinetics, pharmacodynamics and safety of apixaban,
J Clin Pharmacol. 2015. doi: 10.1002/jcph.633
10. Cockcroft DE, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron. 1976;16(1):31–41.
11. Pursley J, Shen JX, Shuster A, et al. LC–MS/MS determination of
apixaban (BMS-562247) and its major metabolite in human plasma:
an application of polarity switching and monolithic HPLC column.
Bioanalysis. 2014;6:2071–2082.
12. Velenosi TJ, Urquhart BL. Pharmacokinetic considerations in
chronic kidney disease and patients requiring dialysis. Expert Opin
Drug Metab Toxicol. 2014;10:1131–1143.
13. Barrett JC, Wang Z, Frost C, Shenker A. Clinical laboratory
measurement of direct factor Xa inhibitors: Anti-FXa assay is
preferable to prothrombin time assay. Thromb Haemost. 2010;104:
1263–1271.
14. Eliquis1 (apixaban tablets) [prescribing information]. Princeton,
NJ: Bristol-Myers Squibb Company; 2014. http://www.accessdata.
fda.gov/drugsatfda_docs/label/2014/202155s009lbl.pdf. Accessed
February 9, 2015.
15. Frost C, Yu S, Nepal S, et al. Apixaban, a direct factor Xa
inhibitor: single-dose pharmacokinetics and pharmacodynamics
of an intravenous formulation. J Clin Pharmacol. 2008;48:
1132.
16. Vakkalagadda B, Frost C, Wang J, et al. Effect of rifampin on the
pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa.
J Clin Pharmacol. 2009;49:1124.
17. Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct factor Xa
inhibitor: single-dose safety, pharmacokinetics, pharmacodynamics
and food effect in healthy subjects. Br J Clin Pharmacol. 2013;75:
476–487.
18. Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and
pharmacodynamics of multiple oral doses of apixaban, a factor Xa
inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76:
776–786.
19. Tanaka H, Nagasawa Y, Matsui I, et al. Pharmacokinetics of
olmesartan medoxomil in hemodialysis patients: little effect of
dialysis upon its pharmacokinetics. Clin Exp Nephrol. 2009;13(1):
61–65.
636
20. Frost CE, Yu Z, Wang J, et al. Single-dose safety and pharmacoki-
netics of apixaban in subjects with mild or moderate hepatic
impairment. Clin Pharmacol Ther. 2009;85 (suppl 1):S34.
21. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body
weight on the pharmacokinetics, pharmacodynamics, safety and
The Journal of Clinical Pharmacology / Vol 56 No 5 2016
tolerability of apixaban in healthy subjects. Br J Clin Pharmacol.
2013;76:908–916.
22. Frost C, Shenker A, Gandhi MD, et al. Evaluation of the effect of
naproxen on the pharmacokinetics and pharmacodynamics of
apixaban. Br J Clin Pharmacol. 2014;78:877–885.