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Pharmacokinetics/Pharmacodynamics

The Journal of Clinical Pharmacology

Lack of Effect of Multiple Doses of 2015, 55(6) 671–679
© 2015 The Authors. The Journal of
Vortioxetine on the Pharmacokinetics and Clinical Pharmacology Published by
Wiley Periodicals, Inc. on behalf of
Pharmacodynamics of Aspirin and Warfarin American College of Clinical Phar-
macology
DOI: 10.1002/jcph.456

Grace Chen, PhD, Wencan Zhang, PhD, and Michael Serenko, MD

Abstract
Vortioxetine is an antidepressant with multimodal activity approved for the treatment of major depressive disorder. Two separate randomized,
placebo-controlled trials evaluated the effects of multiple doses of vortioxetine (10 mg/day) on the pharmacokinetics and pharmacodynamics of aspirin
and warfarin in healthy volunteers. In the aspirin study, subjects received vortioxetine 10 mg or placebo once daily for 14 days, followed by
coadministration with aspirin 150 mg once daily for 6 days, in 2 periods with a crossover design. In the warfarin study, subjects were randomized after
reaching target international normalized ratio (INR) values on warfarin to receive vortioxetine 10 mg or matching placebo once daily for 14 days, with
all subjects receiving a maintenance dose of warfarin (1–10 mg). Vortioxetine had no effect on the steady-state pharmacokinetic parameters of aspirin
or its metabolite salicylic acid, and no statistically significant effect on the inhibition of arachidonic acid-, adenosine-50 -diphosphate-, or collagen-
induced platelet aggregation at any time points. Coadministration of vortioxetine did not alter the pharmacokinetics of (R)- and (S)-warfarin
enantiomers, or the mean coagulation parameters of warfarin treatment alone. Coadministration of vortioxetine doses in healthy volunteers had no
effect on aspirin or warfarin pharmacokinetics or pharmacodynamics. Vortioxetine was well tolerated when coadministered with aspirin or warfarin.

Keywords
vortioxetine, platelet, bleeding, coagulation, pharmacokinetics, drug-drug interaction

Various case reports and epidemiologic studies indicate
that selective serotonin reuptake inhibitors (SSRIs) and
serotonin and norepinephrine reuptake inhibitors (SNRIs)
may be associated with an increased risk of bleeding.1–4
This bleeding risk increases further with concomitant use
of nonsteroidal anti-inflammatory drugs (NSAIDs), anti-
coagulants, and antiplatelet agents.1,5–8 This effect is
thought to be related to platelet serotonin depletion.9
Based on the observation that serotonin reuptake inhibitor
(SRI)-related bleedings most commonly occur in upper
gastrointestinal sites, increased gastric acidity associated
with some SRIs could be another important mechanism
of drug-drug interaction.10 Because warfarin is highly
protein-bound, coadministration with other SSRIs or
SNRIs with high protein binding, such as fluoxetine
and duloxetine, may result in increased levels of free
drug, which could contribute to bleeding-related
complications.11
Vortioxetine was approved by FDA and European
Union (EU) in 2013 for the treatment of major depressive
disorder (MDD).12,13 The pharmacokinetic profile of
vortioxetine is linear and dose-proportional with moder-
ate oral bioavailability, extensive tissue distribution, and a
long elimination half-life.14 Vortioxetine is extensively
metabolized primarily through oxidation via multiple
CYP450 isozymes and subsequent glucuronic acid
conjugation. CYP2D6 is the primary enzyme catalyzing
the metabolism of vortioxetine to its major, pharmaco-
logically inactive, carboxylic acid metabolite Lu
AA34443.15 The plasma protein binding of vortioxetine
in humans is 98%–99% and is independent of the
investigated plasma concentrations of vortioxetine.14
Vortioxetine pharmacological activity is due to the parent
drug rather than to the metabolite. The mechanism of
action of vortioxetine is thought to be related to its
multimodal activity, which is a combination of 2
pharmacological modes of action: direct modulation
of receptor activity and inhibition of the serotonin
Takeda Development Center Americas, One Takeda Parkway,
Deerfield, IL, USA
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
modifications or adaptations are made.
Submitted for publication 14 October 2014; accepted 29 December
2014.
Corresponding Author:
Grace Chen, PhD, Scientific Director, Clinical Pharmacology, Takeda
Development Center Americas, One Takeda Parkway, Deerfield,
IL 60015
Email: grace.chen@takeda.com

672
transporter. In vitro studies indicate that vortioxetine is a
5-HT3A, 5-HT7, and 5-HT1D receptor antagonist, a
5-HT1B receptor partial agonist, a 5-HT1A receptor agonist,
and an inhibitor of the 5-HT transporter.16,17 In vivo studies
in rats demonstrated that vortioxetine enhances levels of
serotonin, noradrenaline, dopamine, acetylcholine, and
histamine in specific areas of the brain.16–18
Aspirin inhibits platelet aggregation and is the
mainstay of secondary antithrombotic treatment. In
high-risk patients, low-dose aspirin (75–150 mg) reduced
the risk of cardiovascular events by 32%.19 Aspirin is
rapidly metabolized via carboxylesterases to salicylic acid
with subsequent conjugation to form a phenolic glucuro-
nide, an acyl glucuronide, and a number of minor
metabolites. Warfarin is a widely prescribed oral
anticoagulant and has established efficacy for the
prevention of thromboembolic events in patients with
chronic atrial fibrillation, prosthetic heart valves, and
coronary artery disease.20–22 Warfarin is a racemic
mixture of (R)- and (S)-enantiomers and is metabolized
almost entirely by hepatic CYP enzymes in a partially
stereo-specific manner. Stereo-selective metabolism pri-
marily by CYP2C9 leads to hydroxylation of (S)-
warfarin.23 Multiple CYP isozymes are involved in the
metabolism of (R)-warfarin.24 Because vortioxetine is
metabolized primarily by the CYP2D6 isoenzyme, and
vortioxetine and its metabolites showed low potential ([I]/
Ki <0.1) for clinically meaningful CYP inhibition for all
CYP isozymes investigated (CYP1A2, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4/5) (unpublished results), coad-
ministration of vortioxetine is unlikely to affect the
metabolic pathways of either aspirin or warfarin.25
SSRIs and SNRIs are reported to potentially increase
the risk of bleeding events, and concomitant use of
aspirin, NSAIDs, warfarin, and other anticoagulants with
these drugs may potentiate this risk.1–8 The objectives of
the current studies were to evaluate the effects of multiple
vortioxetine doses on the pharmacokinetics and pharma-
codynamics of aspirin/salicylic acid and the (R)- and (S)-
warfarin enantiomers.
Methods
Both studies were performed in accordance with the
World Medical Association Declaration of Helsinki and
the International Conference on Harmonisation Tripartite
Guidelines for Good Clinical Practice. The studies were
approved by the institutional review boards of participat-
ing facilities, and all subjects provided written informed
consent.
Design
Aspirin study. This randomized, single-blind, placebo-
controlled, crossover study was designed to assess the
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The Journal of Clinical Pharmacology / Vol XX, No 6 (2015)
effect of multiple doses of vortioxetine on the aspirin-
induced inhibition of platelet aggregation. The study also
evaluated the effects of vortioxetine coadministration on
the pharmacokinetics of aspirin and vice versa. In period
1, 28 subjects were randomized to 1 of the 2 sequences in
which vortioxetine 10 mg or matching placebo was
administered once daily in the morning for 14 days
(days 1–14), followed by coadministration with aspirin
150 mg once daily for 6 days (days 15–20). Following a
21-day washout, in period 2, subjects received the
alternative treatment.
Warfarin study. This randomized, placebo-controlled,
parallel-design study investigated the effect of vortiox-
etine on the multiple-dose pharmacokinetics and phar-
macodynamics of warfarin. Sixty subjects, all of whom
underwent a warfarin titration period (days –9 to –1), were
randomized to 1 of the 2 treatment groups described
below. To be eligible for entry into the coadministration
period, subjects were required to have at least 3
consecutive days of a stable warfarin dose during the
titration period, as well as a target international normal-
ized ratio (INR) value between 1.2 and 1.8 maintained
through day –1. During the coadministration period,
subjects received a maintenance dose of warfarin (1–
10 mg), with either vortioxetine 10 mg or matching
placebo, once daily for 14 days (ie, days 1–14).
Subjects
Aspirin study. Eligible subjects included healthy males
and females aged 18–45 years. Subjects were excluded if
they had any blood dyscrasias, abnormal blood coagula-
tion parameters, or bleeding disorders. In addition,
subjects were not allowed to take medications known to
affect platelet function within 28 days prior to and
throughout the study.
Warfarin study. Healthy males and females aged 18–55
years were eligible for participation in this study.
Inclusion and exclusion criteria were the same as those
used in the aspirin study.
Blood Sample Collection Schedule for Pharmacokinetic/
Pharmacodynamic Analyses
Aspirin study. For the pharmacokinetic analysis of
aspirin and salicylic acid, blood samples were collected
predose; at 10, 30, and 45 minutes postdose; and at 1, 2, 4,
6, 8, 10, 12, and 24 hours postdose on day 20 in each
treatment period. Blood samples for pharmacokinetic
analysis of vortioxetine were collected on days 14 and 20
predose and at 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose.
Blood samples for assessing pharmacodynamic param-
eters were obtained at screening and at baseline; on days
14, 15, and 20 predose; and at 2 and 8 hours postdose.
Warfarin study. For the plasma concentration determi-
nations of warfarin and vortioxetine, blood samples were
collected on day –1 (warfarin only) and day 14 predose,

Chen et al
and at 0.5 (warfarin only), 1, 2, 4, 6, 8, 10, 12, and 24 hours
postdose. Prothrombin time (PT) and INR blood samples
were collected on days –8 through –2; on days 1 through
13 at 5 and 12 hours postdose; on days 15 through 18 at
approximately the same time that the 5- and 12-hour
postdose collections were obtained on the previous dosing
days; on days –1 and 14 predose; and at 2, 4, 6, 8, 10, 12,
and 24 hours postdose.
Pharmacokinetic Analysis
The pharmacokinetic parameters calculated for vortiox-
etine, aspirin, salicylic acid, and (R)- and (S)-warfarin
included area under the plasma concentration-time curve
from time 0 to 24 hours (AUC0–24), maximum plasma
concentration (Cmax), and time to Cmax (Tmax). Minimum
plasma concentration (Cmin) was also calculated for (R)-
and (S)-warfarin. Pharmacokinetic parameters were
derived by noncompartmental analysis using WinNon-
Lin1 (Version 5, Pharsight Corp, Cary, North Carolina).
Actual blood-sampling times relative to dosing were used
in the computation of all plasma pharmacokinetic
parameters. Cmax and Tmax were obtained directly from
the plasma concentration-time profiles.
Pharmacodynamic Analysis
Aspirin study. Pharmacodynamic parameters included
platelet-aggregation inhibition induced by arachidonic acid
(AA), adenosine-50 -diphosphate (ADP), or collagen. At
each time point (predose and 2 and 8 hours postdose), the
percentage platelet-aggregation inhibition was assessed for
the following concentrations: AA 1.5 mM; ADP 2.5 and
5 mM; and collagen 2 and 5 mM. Platelet-aggregation
inhibition was based on the percent inhibition from
baseline (ie, 100  [(baseline  postbaseline)/baseline]).
Warfarin study. The effect of vortioxetine on warfarin
pharmacodynamics was evaluated using PT/INR meas-
urements at various time points throughout the study.
Measurements included the area under INR time curve
from time 0 to 24 hours postdose (AUCINR) and the
maximum observed INR value (INRmax).
Statistical Analyses
Aspirin study. Descriptive statistics were used to
summarize standard pharmacokinetic parameters. Statisti-
cal inference to evaluate the effect of vortioxetine on the
pharmacokinetics of aspirin and salicylic acid was based
on an analysis of variance (ANOVA) model with fixed
effects for sequence, period, and treatment, and a random
effect for subject nested within sequence. This analysis
was performed on the natural logarithms of AUC0–24 and
Cmax of aspirin and salicylic acid on day 20, with or
without vortioxetine coadministration. The 90% confi-
dence interval (CI) of the ratio of the least squares (LS)
means was obtained by determining the antilog of the
90%CI for the differences between the test treatment
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673
(vortioxetine þ aspirin) and the reference treatment
(placebo þ aspirin) on the natural logarithmic scale.
Warfarin study. Descriptive statistics were used to
summarize standard pharmacokinetic parameters. The
effect of vortioxetine on the steady-state (day 14)
pharmacokinetics of (R)- and (S)-warfarin was assessed
by an analysis of covariance (ANCOVA) model. The 90%
CIs of the ratios for the test treatment (vortioxetine þ
warfarin) mean relative to the reference treatment
(placebo þ warfarin) mean were obtained by determining
the antilog of the 90%CIs for the difference between the
means of test and reference treatments on the natural
logarithmic scale. To assess the effects of multiple doses
of (after 14 days of dosing) vortioxetine on the
pharmacodynamics of warfarin, an ANCOVA was
performed in which values from coadministration of
vortioxetine and warfarin were compared with those of
warfarin alone; AUCINR and INRmax were dependent
variables, treatment was a fixed effect, and the baseline
AUCINR and INRmax were covariates. Differences in the
pharmacodynamic parameters and 95%CIs were generat-
ed for the treatment groups.
Results
Subject Disposition
Aspirin study. Fifteen men and 13 women were
enrolled. The mean age was 31.8 years, and most subjects
were white (24 of 28; 85.7%). No clinically meaningful
differences were observed across treatment sequences for
any baseline demographic trait. Demographic and
baseline characteristics are summarized in Table 1.
Warfarin study. Sixty subjects were enrolled.
However, 6 of them did not maintain the target INR
value for 3 consecutive days prior to day –1 and therefore
were withdrawn from the study. Of the remaining 54
subjects, 29 were male and 25 were female; the mean age
was 39.9 years (Table 1). No clinically meaningful
differences were observed across treatments for any of the
demographic or baseline characteristics.
Pharmacokinetics
Aspirin study. The mean plasma concentrations of
aspirin and salicylic acid were similar when aspirin
was administered with and without vortioxetine
(Figure 1). The exposure to aspirin and salicylic acid
was similar after administration of aspirin alone and
after coadministration of vortioxetine 10 mg plus
aspirin; 90%CI intervals of test-to-reference ratios
for AUC0–24 and Cmax were within the 80%–125%
no-effect boundary (Figure 2). The mean steady-state
pharmacokinetic parameters of vortioxetine are sum-
marized in Table 2.
Warfarin study. With respect to mean (R)- and (S)-
warfarin plasma-concentration profiles, the patterns
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674 The Journal of Clinical Pharmacology / Vol XX, No 6 (2015)

Table 1. Demographic and Baseline Characteristics

Aspirin Study Warfarin Study

Sequence I Sequence II Overall Warfarin þ Vortioxetine Warfarin þ Placebo Overall

Characteristic (n ¼ 14) (n ¼ 14) (N ¼ 28) (n ¼ 27) (n ¼ 27) (N ¼ 54)

Sex, n (%)
Male 8 (57) 7 (50) 15 (54) 12 (44) 17 (63) 29 (54)
Female 6 (43) 7 (50) 13 (46) 15 (56) 10 (37) 25 (46)
Mean age, yr (SD) 29.6 (5.0) 33.9 (7.3) 31.8 (6.5) 41.2 (7.7) 38.7 (8.8) 39.9 (8.3)
Race, n (%)
Black 1 (7) 3 (21) 4 (14) 3 (11) 3 (11) 6 (11)
White 13 (93) 11 (79) 24 (86) 24 (89) 24 (89) 48 (89)
Mean weight, kg (SD) 72.9 (12.11) 68.2 (10.1) 70.5 (11.2) 74.2 (10.8) 73.8 (10.2) 74.0 (10.4)
Mean height, cm (SD) 174.9 (9.5) 172.6 (9.1) 173.8 (9.2) 166.3 (8.8) 168.6 (8.5) 167.4 (8.6)
Mean BMI, kg/m2 (SD) 23.7 (2.82) 22.8 (2.3) 23.3 (2.6) 26.7 (2.5) 25.9 (2.5) 26.3 (2.5)

Sequence I: subjects received vortioxetine þ aspirin and then placebo þ aspirin. Sequence II: subjects received placebo þ aspirin and then vortioxetine þ aspirin.
SD, standard deviation.
BMI, body mass index.

were similar for subjects who received warfarin

alone and subjects who received vortioxetine plus
warfarin (Figure 3). Statistical analysis of dose-
normalized (R)- and (S)-warfarin pharmacokinetic
parameters showed that the pharmacokinetics of plasma
(R)- and (S)-warfarin were similar when warfarin was
coadministered with or without vortioxetine (Figure 2).
The 90%CIs of the test-to-reference ratios for AUC0–24,
Cmax, and Cmin for (R)- and (S)-warfarin were all within
the 80%–125% no-effect boundary. The mean steady-
state pharmacokinetics of vortioxetine in this study are
summarized in Table 2.

Figure 1. Mean (SD) plasma concentrations of (A) aspirin and (B)
salicylic acid, administered alone or in combination with vortioxetine.
Pharmacodynamics
Aspirin study. Consistent with the lack of pharmaco-
kinetic effect on aspirin, the pharmacodynamic param-
eters for aspirin, as measured by the percentages of
inhibition of AA-, ADP-, or collagen-induced platelet
aggregation, were not noticeably different between
vortioxetine 10 mg þ aspirin 150 mg and placebo þ
aspirin 150 mg. This is reflected in the overlapping of
the means and standard error bars over time (at days 14,
15, and 20) in Figure 4A, 4B, and 4 C, respectively. The
data points (mean  standard error) on each sampling
day in these figures refer to the platelet-aggregation
inhibition at 8 hours postdose (approximately the
peak time of plasma vortioxetine concentration)
using the highest concentrations of AA, ADP, and
collagen evaluated. As expected, the inhibitory effect
of aspirin on the AA-, ADP-, or collagen-induced
platelet aggregation was evident from the start of
administration of aspirin on days 15–20, and the
magnitude of the inhibition was markedly greater
than the uncertainty associated with the measures
(reflected by the standard errors in these figures).
Similar trends were also observed at other time points
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Chen et al 675

Figure 2. Effect of multiple doses of vortioxetine on the pharmacokinetics of (R)- and (S)-warfarin, aspirin, and salicylic acid (data presented as
LS mean ratio  90%CI).

(ie, predose and 2 hours) and for the lower inducer
concentrations evaluated (data not included). These
results indicate that vortioxetine had no significantly
synergistic effects with aspirin on platelet aggregation
at any time points assessed, regardless of the inducers
evaluated.
Warfarin study. The mean INRmax and AUCINR profiles
were similar for the 2 treatment groups at the end of the
warfarin titration period and after 14 days of administra-
tion of either warfarin alone or coadministration of
vortioxetine and warfarin. Statistical analyses (Table 3)
indicate that the LS mean difference between treatment
groups was very small (–0.04 for INRmax and –0.91 for
AUCINR) and not significantly different (corresponding
P values of .667 and .584). The 95%CIs of the differences
show that the estimated differences between treatments are
very small (within 3% of means) and the bounds of the CIs
also indicate that even accounting for uncertainty, the
difference between treatments is limited to 12%–15% for
either INRmax or AUCINR.

Table 2. Pharmacokinetic Parameters of Vortioxetine After Multiple Daily Doses of Vortioxetine 10 mg in the Aspirin and Warfarin Drug-
Interaction Studies

Aspirin Study Warfarin Study

Vortioxetine Alone (Day 14) Vortioxetine þ Aspirin (Day 20) Vortioxetine þ Warfarin (Day 14)

Parameter Mean (%CV) (N ¼ 28) Mean (%CV) (N ¼ 28) Mean (%CV) (N ¼ 26)

AUC0–24 (ng  h/mL) 322.9 (31.9) 322.3 (30.5) 414.7 (44.0)

Cmax (ng/mL) 17.0 (31.5) 16.9 (30.8) 21.2 (43.4)
Tmax (hour)a 8.0 (6.0, 12.0) 8.0 (6.0, 12.0) 10.0 (8.0, 12.0)

AUC0–24, area under the plasma concentration–time curve from time 0 to 24 hours; Cmax, maximum observed plasma concentration; Tmax, time at which Cmax
occurred.
a
Median (range).

676
Figure 3. Mean (SD) plasma concentrations of (A) (R)-warfarin and (B)
(S)-warfarin, administered alone or in combination with vortioxetine.
Safety and Tolerability
Treatment was generally well tolerated in both studies.
Adverse events that occurred in more than 2 subjects in
any treatment group of either study were nausea,
abdominal pain, diarrhea, and constipation (Table 4).
Most adverse events were considered mild or moderate in
intensity; no serious adverse events were reported in
either study. One subject randomized to the placebo þ
warfarin group was withdrawn from the study on day 2
due to elevation of liver enzymes. No subjects discon-
tinued treatment because of an adverse event in the aspirin
study. There were no clinically meaningful changes in
laboratory values, electrocardiograms, vital signs, or
physical examination results.
Discussion
Various studies have suggested an association between
SSRIs/SNRIs and an increased risk of bleeding.1–4 The
bleeding risk increases further when SSRIs/SNRIs are
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The Journal of Clinical Pharmacology / Vol XX, No 6 (2015)
used concomitantly with NSAIDs, anticoagulants, and
antiplatelet agents.1,5–8 Potential mechanisms that
underlie the bleeding risk associated with medications
that affect the serotonergic system may include
inhibition of serotonin uptake by platelets, SRI-induced
increases in gastric acid secretion, and modulation of
the CYP450 metabolism.9,10,26 Certain SSRIs and
SNRIs with high protein binding (eg, fluoxetine,
duloxetine), when coadministered with another highly
bound drug (eg, warfarin), may also increase the free
plasma drug concentrations via displacement of protein-
bound drug, potentially increasing the risk of adverse
events.11,27,28
Because one of the pharmacological modes of action
for vortioxetine is inhibition of the serotonin transporter,
the current studies were designed to evaluate the effect of
multiple dosing of vortioxetine on the pharmacokinetics
and pharmacodynamics of aspirin or warfarin in healthy
subjects. Although the use of drugs that interfere with
serotonin reuptake inhibition has been reported to
increase the risk of bleeding events, coadministration of
multiple daily doses of a 10-mg dose of vortioxetine with
stable doses (1–10 mg) of warfarin showed no difference
in the INR or prothrombin times compared to matching
placebo. Vortioxetine at the 10-mg dose when added to
the 150-mg dose of aspirin did not change AA-, ADP-, or
collagen-induced platelet aggregation. The lack of
pharmacodynamic drug interaction potentials between
vortioxetine and aspirin or warfarin is consistent with the
absence of pharmacokinetic interactions between vorti-
oxetine and these 2 concomitant medications. Both
vortioxetine and warfarin are highly bound to plasma
proteins (98% and 99%, respectively), the fact that total
warfarin (protein bound plus free drug) pharmacokinetics
for both (R)- and (S)-warfarin, as well as INR and
prothrombin values, did not change significantly with
coadministration of these 2 drugs suggested that
vortioxetine did not increase the free drug concentration
of warfarin appreciably due to protein displacement.
Moreover, the coadministration of vortioxetine with
aspirin or warfarin was well tolerated, with no indication
of an increased risk of adverse events in these studies. As
pharmacokinetics of vortioxetine was linear over the dose
range of 2.5–60 mg/day and similar between healthy
subjects and MDD patients, the lack of pharmacokinetic
and pharmacodynamic effects in these studies suggests
the bleeding risk from the potential drug-drug interactions
in the patient population is expected to be low for
vortioxetine. In the vortioxetine clinical safety and
efficacy registration studies, the chronic use of NSAIDS,
including aspirin, and chronic and episodic use of
anticoagulants, including warfarin, was prohibited. Based
on the pooled safety analysis across all short-term clinical
studies over the dose range of 1–20 mg/day in over 4,681
patients, the overall incidence of hemorrhage as a
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Chen et al 677

Figure 4. Inhibition of platelet aggregation induced by (A) arachidonic acid (AA) 1.5 mM, (B) adenosine-50 -diphosphate (ADP) 5 mM, and (C) collagen
5 mM at 8 hours by aspirin, with and without concomitant vortioxetine. Data are mean  standard error.

treatment-emergent adverse event (TEAE) was low and
similar between the overall vortioxetine treatment group
and placebo (1.7% and 1.2%, respectively), with no dose-
related increase in adverse events observed among the
individual vortioxetine treatment groups.29 All events in
the individual vortioxetine dose groups were nonserious.
The overall pattern of hemorrhage as a TEAE in the open-
label long-term extension studies was similar to that seen
in the short-term clinical trials. Laboratory tests under-
taken throughout the vortioxetine clinical development
program indicated that the platelet count did not change
over time. Based on these results, the bleeding risk
associated with vortioxetine treatment in MDD patients is
considered low.
In conclusion, these drug-drug interaction studies
suggest that vortioxetine has no impact on the pharmaco-
kinetics of aspirin or warfarin and does not affect
coagulation parameters when coadministered with either
drug. However, due to the small sample size and the use of
healthy volunteers in these studies, large epidemiologic

Table 3. The Effects of Multiple Doses of 10 mg Vortioxetine on Pharmacodynamic Parameters of Warfarin

LS Mean

Warfarin þ Vortioxetine 10 mg Warfarin þ Placebo LS Mean 95%CI

Parameter (Test: n ¼ 26) (Reference: n ¼ 26) Difference Difference P Value

Observed
INRmax (ratio) 1.51 1.54 –0.04 –0.19, 0.11 .667
AUCINR (hour*ratio) 34.96 35.87 –0.91 –3.66, 1.85 .584

AUCINR, INR time curve from time 0 to 24 hours postdose; INRmax, maximum observed INR value; LS, least squares.
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678 The Journal of Clinical Pharmacology / Vol XX, No 6 (2015)

Warfarin þ Placebo
studies in depressed patients may be needed to fully

(52%)

(15%)

(11%)
confirm the lack of association between vortioxetine and

(n ¼ 27)

(7%)

(4%)
(4%)

(4%)
Stable Warfarin Dose Phase the increased risk of bleeding when coadministered with

2
4
1
1
3
0
1
0
0
14
NSAIDs and anticoagulants.

Acknowledgments
Warfarin þ Vortioxetine

This study was supported by the Takeda Pharmaceutical

Company, Ltd. and H. Lundbeck A/S. Assistance with writing
(70%)
(19%)
(15%)

(11%)
(11%)
(n ¼ 27)

(7%)

(7%)
(7%)
and manuscript preparation was provided by Bret Fulton, PhD,
of The Medicine Group and funded by the Takeda Pharmaceu-
19
5
4
2
3
3
2
2
0
0
tical Company, Ltd. and H. Lundbeck A/S. Grace Chen, Wencan
Zhang, and Michael Serenko each contributed to the concept,
data analysis, drafting, critical revisions, and approval of the
Warfarin Study

Warfarin þ Placebo

article, had full access to all the data in the study, and take
responsibility for the integrity of the data and the accuracy of the
(n ¼ 27)

3 (11%)

data analysis.
0
0
0
0
0
0
0
0
0

Declaration of Conflicting Interests

Warfarin Titration Period

All authors have completed the Unified Competing Interest form

Warfarin þ Vortioxetine

at www.icmje.org/coi_disclosure.pdf (available on request from

the corresponding author) and declare: GC, WZ, and MS had
(n ¼ 27)

(15%)

funding and study support from Takeda Development Center

(4%)

(4%)
(4%)

Americas and H. Lundbeck A/S for the submitted work, and

4
0
0
1
0
0
1
1
0
0

assistance with writing and manuscript preparation by Bret

Fulton, PhD, and Philip Sjostedt, BPharm, of The Medicine
Group. GC and WZ are employees of Takeda Development
Center Americas for the previous 3 years. At the time of these
Warfarin
Table 4. Summary of Treatment-Emergent Adverse Events (Occurring in 2 Subjects in Either Study)

(n ¼ 6)

studies, MS was an employee of Takeda Pharmaceutical

0
0
0
0
0
0
0
0
0
0

Company, Ltd. for the previous 3 years. GC, WZ, and MS

have no other relationships or activities that could appear to have
Placebo þ Aspirin

influenced the submitted work.

(Days 15–20)
(n ¼ 28)

2 (7%)

1 (4%)

1 (4%)

References
0
0

0
0
0
0

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