Expert Opinion on Drug Metabolism & Toxicology

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Lisdexamfetamine: chemistry,
pharmacodynamics, pharmacokinetics, and
clinical efficacy, safety, and tolerability in the
treatment of binge eating disorder

Kristen Ward & Leslie Citrome

To cite this article: Kristen Ward & Leslie Citrome (2018) Lisdexamfetamine: chemistry,
pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment
of binge eating disorder, Expert Opinion on Drug Metabolism & Toxicology, 14:2, 229-238, DOI:
10.1080/17425255.2018.1420163

To link to this article: https://doi.org/10.1080/17425255.2018.1420163

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EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2018
VOL. 14, NO. 2, 229–238
https://doi.org/10.1080/17425255.2018.1420163

DRUG EVALUATION

Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical

efficacy, safety, and tolerability in the treatment of binge eating disorder
Kristen Warda and Leslie Citromeb
a
University of Michigan College of Pharmacy, Ann Arbor, MI, USA; bPsychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY USA

ABSTRACT ARTICLE HISTORY

Introduction: The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were Received 26 September 2017
recently expanded to include treatment of moderate to severe binge eating disorder (BED). Accepted 18 December 2017
Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the KEYWORDS
clinical trials investigating the efficacy and safety of this medication for the management of BED. Binge eating;
Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for d-amphetamine;
the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-ampheta- LDX; lisdexamfetamine;
mine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of pharmacodynamics;
synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases pharmacokinetics; SPD489;
in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then safety; stimulant; tolerability
further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX
demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at
doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight
loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities,
cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of
abuse needs to be assessed prior to prescribing.

1. Introduction patients with BED range from slightly less than 50% [3] to
approximately 70% [4], obese patients with BED are more
Binge eating disorder (BED) can be summarized as repetitive
likely to have decreased functional capacity and quality of
episodes of eating more food than would normally be con-
life than obese patients without BED [4].
sumed by an average person in the same setting, without
American Psychiatric Association treatment guidelines,
compensatory purging or exercising, and feeling unable to
last published in 2006, strongly recommend the use of
control this behavior [1]. Although the BED diagnosis was
cognitive behavioral therapy (CBT) and guided self-help
officially recognized for the first time in DSM-5, the DSM-IV
programs in the treatment of BED, and there is adequate
and the text revision version of the DSM-IV (DSM-IV-TR) [2]
evidence to support the off-label use of antidepressants,
contained preliminary BED diagnostic criteria that were
particularly selective serotonin reuptake inhibitors (SSRIs),
commonly used in research studies, including those dis-
and the mood stabilizer topiramate [5]. Topiramate [6], but
cussed in this review. A key difference between DSM-5 and
not antidepressants [7], has also been associated with
DSM-IV-TR criteria is that the required average binge eating
improved response to CBT in the treatment of BED. In
(BE) episode occurrence was modified from twice weekly for
2015 lisdexamfetamine dimesylate (LDX) became the first
the past 6 months, to once weekly for the past 3 months
medication approved by the United States Food and Drug
[1,2]. BED is the most common eating disorder, with an
Administration (FDA) for the treatment of moderate to
estimated lifetime prevalence of 2.8% (3.5% females, 2.0%
severe BED (Box 1) [8]. As it can be often difficult for
males) [3], representing a large number of patients who
patients to access therapy providers specialized in eating
would potentially benefit from treatment for BED over the
disorders in their community, this development addresses a
course of their lifetime.
significant unmet medical need for more effective drug
An important consideration when selecting treatment
therapies that are not associated with increased weight, as
strategies for patients with BED is the high rate of comorbid
with many antidepressants, or the potential for cognitive
psychiatric diagnoses. Results from the National
impairment, as with topiramate.
Comorbidity Survey Replication (NCS-R) of approximately
In this review, we compile and present the available evi-
10,000 people noted that 79% of responders with BED
dence on the chemistry, mechanism of action, and pharmaco-
met criteria for at least one comorbid DSM-IV diagnosis,
kinetics of LDX, and will describe clinical trials investigating the
and that 49% met criteria for at least three additional
efficacy, tolerability and safety of LDX for the treatment of BED.
diagnoses [3]. Additionally, while observed obesity rates in

CONTACT Leslie Citrome citrome@cnsconsultant.com Psychiatry and Behavioral Sciences, New York Medical College, 11 Medical Park Drive, Suite
106, Pomona, NY 10970, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
230 K. WARD AND L. CITROME

Box 1. Drug summary.

Drug name (generic)
Phase (for indication under
discussion)
Pharmacology description/
mechanism of action
Route of administration
Chemical structure
Lisdexamfetamine dimesylate
Product is approved for use
Stimulant/Prodrug of d-amphetamine, a non-catecholamine sympathomimetic amine, that increases synaptic
concentration of norepinephrine and dopamine via multiple mechanisms
Oral
(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate

Pivotal trials One Phase II [49], and two Phase III [50], 11–12 week randomized controlled trials in patients with moderate to severe
BED. All trials showed improvement over placebo in reducing binge eating days per week at 50 or 70 mg/day doses.

2. Search criteria
In July 2017, the US National Library of Medicine’s PubMed
resource (http://www.ncbi.nlm.nih.gov/pubmed/) and the
EMBASE (Elsevier) commercial database were queried with
the terms ‘lisdexamfetamine’ OR ‘LDX’ OR ‘SPD489’ to identify
literature describing the pharmacodynamic, pharmacokinetic,
pharmacogenomic, or chemical properties of LDX. The term
‘binge’ was included with filters for articles with human clinical
trials to identify primary literature describing the efficacy and
safety of LDX for the treatment of BED. Concurrently, clinical
trial registries http://www.clinicaltrials.gov and http://www.clin
icaltrialsregister.eu were searched with the filters ‘lisdexamfe-
tamine’ and ‘binge’ to identify all clinical trials involving LDX
for the treatment of BED. This amounted to six completed, and
one in-progress, clinical trials. Finally, the manufacturer of LDX
(Shire, Dublin, Ireland) was contacted to obtain copies of
posters that have been presented at scientific congresses.
3. Overview of LDX
3.1. Introduction to drug product
LDX is a central nervous system (CNS) stimulant that first
received FDA approval in 2007, as a schedule II medication,
for the treatment of attention-deficit/hyperactivity disorder
(ADHD) in children [8]. This was followed by approval for
the treatment of ADHD in adults (2008) and adolescents
(2010), and then for the maintenance treatment of ADHD
in adults in 2012 [8]. LDX was originally investigated for use
in managing BED following the observation that BED and
ADHD share neurobiological and psychological features,
including dysregulation in dopamine signaling [9] and
impulsivity [10–12]. For a review of the neurobiological
changes underlying BED, see Kessler 2016 [13]. LDX influ-
ences the concentration of some of the neurotransmitters
that are associated with BED, decreases impulsivity in
patients with BED [10,14], and has a propensity to cause
weight loss [15], which may be beneficial for obese BED
patients.
3.2. LDX chemistry and mechanism of action
LDX is an inactive pro-drug of d-amphetamine that is covalently
bonded to L-lysine [15]. D-amphetamine is a non-catecholamine
sympathomimetic amine, the more potent dextrorotatory isomer
of amphetamine [16], formed from LDX when peptidases in red
blood cells hydrolyze the parent compound [17,18]. In vitro
studies suggest this activation process is efficient even in the
setting of low hematocrit and sickle cell disease [18,19].
The exact mechanism by which LDX improves symptoms
of BED is unknown, but is likely related to d-amphetamine’s
ability to increase brain interstitial concentrations of norepi-
nephrine and dopamine through action at dopamine and
norepinephrine membrane transporters [20–23] involving
factors such as extracellular sodium (Na+) binding [24] and
intracellular calcium (Ca2+) levels [25]. Dopamine concentra-
tions may also be increased through non-dopamine trans-
porter-related mechanisms involving norepinephrine
transmission [26]. Amphetamine also binds with less affinity
to the serotonin transporter [21]. An in vitro study with
amphetamine and human monoamine transporters identi-
fied the following binding affinities for the dopamine, nor-
epinephrine, and serotonin transporters (inhibitory constant
[KI] in µM ± standard error of the mean [SEM]), respectively:
0.64 ± 0.14, 0.07 ± 0.01, and 38.46 ± 3.84 [21].
Another potential mechanism of action of LDX for the
treatment of BED is through d-amphetamine’s effect at the
trace amine-associated receptor 1 (TAAR1) [27]. TAAR1 is a
G-protein-coupled receptor that is activated by endogenous
trace amines, such as tyramine, tryptamine, and octopamine;
regulates dopamine; and moderates response to ampheta-
mine and other psychostimulants [28]. TAAR1 agonism as a
mechanism of improving BED symptoms was supported in a
recent rat study that demonstrated a TAAR1 agonist reduced

the consumption of palatable food, without reducing regular
chow intake, in normal and aversive settings [29].
3.3. Pharmacokinetics
3.3.1. Absorption
Table 1 provides a summary of pharmacokinetic parameters of
LDX that were measured in adults with ADHD who had been
taking an average LDX dose (SD) of 62.5 (14.2) for 5 weeks
[30]. LDX is available as capsules and chewable tablets, and
the capsule can be opened and dissolved in water without
decreasing the overall amount absorbed, as measured by area
under the curve (AUC) [31]. Absorption of LDX from the gas-
trointestinal tract is rapid [18], and when taken with food, the
time to maximum serum concentration (tmax) is delayed by
approximately one hour [31]. Additionally, gastric pH does not
appear to impact the absorption of d-amphetamine from LDX,
as measured by the maximum serum concentration (Cmax) and
AUC in patients who were exposed to LDX with, and without,
the proton pump inhibitor omeprazole [32].
3.3.2. Distribution
There is little data on the distribution of LDX. A small pharmaco-
kinetic study of healthy participants, the majority male, described
d-amphetamine as following a one-compartment model of dis-
tribution with a plasma volume (95% CI) of 377 L (326–428) [34].
This is a relatively large volume of distribution, signifying that the
drug leaves the intravascular space and distributes to most
tissues in the body. In a population of patients with high rates
of obesity, this may have implications for dose requirements, but
it is difficult to predict because lipophilic drugs do not always
require dosage adjustments in obesity [35]. The extent of LDX
plasma protein binding is not known; however, an in vitro equili-
brium dialysis study of amphetamine noted a mean percentage
of bound amphetamine in humans (±SEM) to be 14.5 ± 0.9, these
results were independent of drug concentration and did not
differ significantly when the plasma was uremic [36]. This indi-
cates that protein binding is unlikely to be clinically significant,
with respect to impact on free amphetamine in the plasma.
3.3.3. Metabolism
As mentioned previously, LDX is transformed by peptidases in
red blood cells to form d-amphetamine. D-amphetamine is
further metabolized in the liver to hippuric acid, benzoic
acid, norephedrine, 4-hydroxynorephedrine, and benzyl
methyl ketone [15,37]. Although LDX itself is not metabolized
by cytochrome (CYP) P450 enzymes, amphetamine is primarily
metabolized by CYP2D6 [38–40].
Table 1. Summary of lisdexamfetamine and d-amphetamine pharmacokinetics.a
Pharmacokinetic parameter Lisdexamfetamine D-amphetamine
Cmax (ng/mL) 25.0 67.9
Tmax (hours) 1.5 4.4
AUC (ng/mL × hours) 45.9 641.6
T1/2 0.5 17
a
Data summarized from Adler et al. 2017 [33]
AUC: area under the curve, Cmax: maximum serum concentration, Tmax: time to
maximum serum concentration, T1/2: time when half of the concentration of
drug in the body is eliminated.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 231
LDX does not appear to significantly inhibit or induce CYP1A2,
2D6, or 3A activity in vivo [41,42], but competitively inhibits
monoamine oxidase (MAO-A Ki 20µM [43]), leading to potentially
significant drug interactions with monoamine oxidase inhibitors
such as selegiline [15]. There is also potential for 2D6 inhibitors to
increase d-amphetamine concentrations, and LDX may contri-
bute to serotonin syndrome risk in patients with multiple med-
ications inhibiting serotonin reuptake, in addition to enhancing
the activity of medications with sympathomimetic activity [15].
Serotonin syndrome occurs in the setting of elevated synaptic
serotonin concentrations, with central and peripheral effects, and
can be mild (gastrointestinal upset, tremors, agitation) to life-
threatening (seizures, hyperthermia, coma, and death) [44].
3.3.4. Excretion
In adults with ADHD, the plasma half-life of LDX is approximately
0.5 h, and the half-life of d-amphetamine is approximately 17.0 h
[30], which allows for once-daily dosing [15]. The majority (96%)
of LDX is excreted renally, mostly as d-amphetamine (41.5%) and
hippuric acid (24.8%), but also 2.2% as intact LDX [45]. Several
dose adjustments are recommended by the manufacturer
related to renal excretion [15]. In patients with glomerular filtra-
tion rates (GFR) 15–30 mL/min/1.73 m2, the dose should be no
more than 50 mg/day, and if GFR is less than 15 mL/min/1.73 m2,
the dose should be no more than 30 mg/day. LDX and d-amphe-
tamine do not appear to be recoverable in dialysate, and there-
fore LDX should not be recommended in patients on dialysis [46].
Additionally, renal excretion appears to be dependent on urine
pH, with higher blood levels of amphetamine observed with
higher urine pH, and may require dose adjustments if a patient
is taking additional medication that changes urine pH [15].
3.4. Pharmacogenetics
Currently, there are no published studies examining the relation-
ship between genetic variability and response to LDX as a treat-
ment for BED. A small study (N = 32) in 2007 noted that a dopamine
transporter gene (DAT1) variant was associated with more appetite
suppression in BED subjects who took the stimulant methylpheni-
date, when compared to control participants with the same geno-
type [47]. Additionally, a recent review highlights a number of
studies suggesting that genetic variability in genes coding for
monoamine transporters, and enzymes that impact monoamine
concentrations, may be associated with response to amphetamine
as it pertains to ADHD response or abuse or dependence potential
[48]. At this point, none of the associations reviewed are supported
by sufficient evidence to warrant dosing recommendation
changes for amphetamine products used to treat ADHD or BED.
4. Clinical trials investigating the use of LDX for the
treatment of BED
4.1. Efficacy
Clinical trials involving the use of LDX for the treatment of BED
are summarized in Table 2. Three randomized, placebo-con-
trolled trials, one phase II and two phase III, were pivotal for
demonstrating the efficacy and safety of LDX for the treatment
of BED [49,50], and ultimately resulted in FDA approval for this
 232

Table 2. Clinical trials determining the efficacy and safety of lisdexamfetamine for binge eating disorder in adults.a
Length (weeks), dose Phase,
Study title (mg/day) Nb Primary outcome Primary outcome results Study period Sponsor, trial IDc, resultsd
A phase 2, multicenter, randomized, double-blind, 11 II Change in log-transformed binge eating ● Placebo: −1.23 May 2011–January 2012 Shire
parallel-group, placebo-controlled, forced-dose 30, 50, or 70 255 days per week, as measured between (SE 0.069) NCT01291173
titration Study to evaluate the efficacy, safety, baseline and week 11 and compared ● 30 mg/day: −1.24 Results on ClinicalTrials.gov and
and tolerability of SPD489 in adults aged to placebo (SE 0.067) published: PMID 25587645
18–55 years with binge eating disorder [49] ● 50 mg/day: −1.46
(SE 0.066), p = 0.008
● 70 mg/day: −1.57
(SE 0.067), p = 0.002
K. WARD AND L. CITROME

The SPD489343, phase 3, multicenter, randomized, 12 III Change from baseline to week 11 or 12 ● Placebo: −2.51 November 2012– Shire
double-blind, parallel-group, placebo-controlled, 50 or 70 374 (visit 8) in number of binge eating (SE 0.125) September 2013 NCT01718483
dose-optimization study to evaluate the efficacy, days per week ● 50 or 70 mg/day: 2012–003309-91
safety and tolerability of SPD489 in adults aged -3.87 (SE 0.124), Results on ClinicalTrials.gov and
18–55 years with moderate to severe binge ● p < 0.001 published: PMID 26346638
eating disorder [50]
The SPD489344, phase 3, multicenter, randomized, 12 III Change from baseline to week 11 or 12 ● Placebo: −2.26 November 2012– Shire
double-blind, parallel-group, placebo-controlled, 50 or 70 350 (visit 8) in number of binge eating (SE 0.137) September 2013 NCT01718509
dose-optimization study to evaluate the efficacy, days per week ● 50 or 70 mg/day: 2012–003310-14
safety, and tolerability of SPD489 in adults aged −3.92 (SE 0.135), Results on ClinicalTrials.gov and
18–55 years with moderate to severe binge p < 0.001 published: PMID 26346638
eating disorder [50]
Lisdexamfetamine in binge eating disorder of 12 III Rate of reduction of mean binge eating ● LDX change from January 2010 – October Linder Center of Hope with
moderate or greater severity [51] 20 to 70 50 days per week baseline – placebo 2012 collaborators Shire and University
change from baseline of Cincinnati
(95% CI) = −0.7 (0.5– NCT01090713
1.0), p = 0.08 Published results:
PMID 27650406
A phase 3, multicenter, open-label, 12 month 53 III 1) Percentage of patients with TEAEs ●Any TEAE: 84.5% August 2012 – October Shire
extension safety and tolerability study of SPD489 50 or 70 599e (week 52) ●Serious TEAE: 2.8% 2014 NCT01657019
in the treatment of adults with binge eating 2) Number with a positive response on ●Active SI: 2 2012–003313-34
disorder [57] the C-SSRS (week 53) ●Non-suicidal self- Results on ClinicalTrials.gov and
injurious behavior: 3 published: PMID 28383364
A phase 3, multicenter, double-blind, placebo- 26 III Time to relapse (2 or more binge days/ ● Relapse criteria was January 2014–April 2015 Shire
controlled, randomized-withdrawal study to 50 or 70 275 week for 2 consecutive weeks with an met for 3.7% of NCT02009163
evaluate the maintenance of efficacy of SPD489 increase in CGI-S ≥ 2) measured from participants on LDX, 2012-004457-88
in adults aged 18–55 years with moderate to 26 weeks after randomization when and 32.1% of the Results on ClinicalTrials.gov and
severe binge eating disorder [52] compared to placebo participants receiving published: PMID 28700805
placebo,
p < 0.001
Effects of lisdexamfetamine on prefrontal brain 12 II Measurement of brain activation in the N/A September 2015– Lindner Center of HOPE with
dysfunction in binge eating disorder 50 or 70 40f ventral prefrontal, striatal, and December 2017 collaborator University of
amygdala with fMRI following food (estimated) Cincinnati
cues NCT02659488
No results available, still recruiting
a
Records identified on ClinicalTrials.gov and clinicaltrialsregister.eu in June 2017.
b
Number of participants included in primary outcome analysis.
c
ClinicalTrials.gov and EU Clinical Trials Register identifiers, as appropriate.
d
PubMed ID provided for published study results, if applicable.
e
N was 599 for the primary outcome of any TEAE, N was 597 for the primary outcome of participants with a positive response on the C-SSRS.
f
Estimated enrollment, trial is still recruiting.
CI: confidence interval; CGI-S: Clinical Global Impression-Severity scale; C-SSRS: Columbia Suicide Severity Rating Scale; SE: standard error; TEAE: treatment emergent adverse event.;

indication (summarized in Table 2, rows 1–3). All three trials
share several similarities: (1) recruited adults 18–55 years old
with moderate to severe BED based on DSM-IV-TR criteria and
experiencing ≥3 BE days/week for at least two consecutive
weeks before baseline, (2) measured change in BE days per
week from baseline to weeks 11 or 12 of treatment, (3) the
majority of participants were white, obese, females, with an
average age of approximately 40 years, (4) adherence was
tracked by counting remaining pills at study visits, (5) efficacy
and safety analyses were completed for all participants who
took one dose of study drug and completed one post-baseline
assessment, and (6) were sponsored by Shire (manufacturer of
branded LDX product).
The Phase II trial was conducted at multiple sites in the
United States [49]. Patients were excluded if (1) their body
mass index (BMI) was <25 or >45 kg/m2; (2) they had used a
medication for weight loss, or a psychostimulant recently (3
and 6 months, respectively); (3) had a history of personal or
familial cardiovascular disease (CVD) that may make them
more sensitive to stimulant side effects; (4) those with a
recent history of substance abuse (not nicotine depen-
dence); or (5) had a Montgomery–Asberg Depression Score
(MADRS) of at least 18 at baseline. Additional exclusion
criteria included comorbid anorexia or bulimia nervosa,
ADHD or another psychiatric disorder, and any history of
psychostimulant abuse or dependence in addition to recent
substance abuse (except nicotine). Patients who had used
antidepressants, sedatives, anxiolytics, antipsychotics, benzo-
diazepines, antihistamines, herbals preparations, or over-the-
counter medications within the last 30 days were also
excluded. Female participants were required to have nega-
tive pregnancy tests and be willing to use contraception.
Eligible participants were randomized (1:1:1:1) into placebo,
30 mg, 50 mg, or 70 mg LDX daily groups. All capsules were
visually identical, and participants randomized to study drug
were started at 30 mg daily, and increased by 20 mg weekly
until they reached their assigned dose, at which time main-
tenance continued for another 8 weeks. The primary efficacy
measure was number of BE days per week, and was ana-
lyzed after log-transformation of the number of BE days per
week (+1). There were an extensive number of secondary
efficacy measures used in this study, including number of BE
episodes per week, 4-week cessation (no binge episodes),
score on the Clinical Global Impressions-Improvement scale
(CGI-I, dichotomized as ratings of 1–2, or 3–7, with lower
numbers denoting improvement in symptoms), the Yale–
Brown Obsessive Compulsive Scale modified for BE (Y-
BOCS-BE), the Barratt Impulsiveness Scale (BIS-11), the
MADRS, and the Hamilton Anxiety Rating Scale.
The primary end point was least squares mean change in
BE days per week from baseline to week 11 (or early termina-
tion). Mixed-effects modeling for repeated measures was used
to analyze data for the primary outcome. About 255 partici-
pants were included in the efficacy analysis. As shown in
Table 2, the primary end point demonstrated significant
improvement over placebo with the 50 and 70 mg/day
doses. The non-transformed BE days per week (SD) changed
from 4.6 (1.25) to 0.5 (1.25), 4.5 (1.28) to 0.4 (0.86), 4.5 (1.44) to
1.0 (1.69), and 4.3 (1.38) to 1.1 (1.45) in the 70 mg/day, 50 mg/
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 233
day, 30 mg/day, and placebo groups, respectively. Among
significant secondary end point outcomes, CGI-I score was
significantly favorable for all dosages of LDX when compared
to placebo (scores of 1 or 2 at week 11).
The two, 12-week, phase III trials investigating LDX efficacy,
safety, and tolerability were structured to have matching
designs and methods (listed in Table 2, with internal assign-
ment classifiers SPD489343 and SPD489344 in their titles) [50].
For ease of reference they will be referred to as study 343 and
344 when they are discussed separately. Both were interna-
tional, randomized, double-blind, placebo-controlled trials.
Inclusion/exclusion criteria that are different from the phase
II trial include a CGI-S score of at least 4 at baseline (indicating
moderate illness, with higher numbers corresponding to more
severe illness), and a modification of the exclusionary BMI
range to <18 kg/m2 (maintaining >45 kg/m2 exclusionary
criterion). Eligible participants were randomized (1:1) to pla-
cebo or dose-optimized LDX. As compared to the phase II trial,
4 weeks, instead of 3, were provided for dose titration. During
dose optimization, patients assigned to LDX began treatment
at 30 mg/day, and after 1 week of treatment were subse-
quently titrated to 50 mg/day. Additional increases to
70 mg/day were made as tolerated and clinically indicated.
Participants could decrease their dose from 70 to 50 mg/day
during the last 2 weeks of the optimization phase. The main-
tenance period lasted 8 weeks.
As in the phase II trial, the primary end point measure was
change from baseline to the end of the maintenance period in
BE days/week, but this value was not log-transformed. A
mixed effect model was used in the primary analysis.
Approximately 60% of participants in the LDX groups of
each study tolerated 70 mg/daily, and the average daily dose
(SD) of LDX was 56.9 (9.72) and 57.6 (9.24) mg/day for study
343 and 344, respectively. A total of 374 participants from
study 343 and 350 participants from study 344 were included
in the primary analysis. Results from both studies identified
significant improvement in LDX’s ability to decrease BE days/
week when compared to placebo.
An additional phase III, placebo-controlled, double-blind,
flexible-dose study was conducted at the Lindner Center of
HOPE in Mason, Ohio [51]. This study was designed before the
previously discussed clinical trials. The flexible dose design
allowed participants to receive doses as low as 20 mg/day
based on tolerability. The primary outcome measure in this
trial was the longitudinal rate of change of BE days/week, and
all 50 participants were included in the primary outcome
analysis. The mean (SD) LDX dose at end point was 59.6
(14.9) mg/day. Results of the primary outcome measure
demonstrated that rate of reduction in BE days/week was
not significantly different between the LDX group and the
placebo group (Table 1), but the secondary end points of
change in BE days/week and episodes/week were different
between the two groups (p = 0.03 and 0.005, respectively).
An additional phase III trial was constructed with the aim of
assessing the maintenance of efficacy of LDX in an interna-
tional, double-blind, placebo-controlled randomized withdra-
wal study [52]. Inclusion/exclusion criteria were similar to
those in studies 343 and 344. Following a 12-week open-
label phase that was modeled after trials 343 and 344,
234 K. WARD AND L. CITROME

participants who were classified as responders (≤1 BE day per Table 3. Treatment-emergent adverse events occurring in at least 5% of parti-
cipants taking lisdexamfetamine in clinical trials for binge eating disorder,
week for 4 consecutive weeks and CGI-S scores ≤2 [borderline separated by trial design.
ill or less]) at week 12 were randomized to placebo, or con- A. Acute, double-blind randomized controlled trialsa
tinued LDX, during a 26-week, double-blind randomized with- TEAE Lisdexamfetamine Placebo
drawal phase. The primary outcome variable was time to N (% out of 594) N (% out of 460)
relapse (≥2 BE days per week for 2 consecutive weeks and Dry mouth 219 (36.9) 32 (7.0)
Headache 86 (14.5) 44 (9.6)
≥2-point CGI-S score increase) from randomized withdrawal Insomnia 90 (15.2) 23 (5.0)
baseline, and was analyzed with a log-rank test. The primary Decreased appetite 70 (11.8) 13 (2.8)
outcome was assessed using participants who had received at Nausea 49 (8.2) 25 (5.4)
Constipation 35 (5.9) 8 (1.7)
least one dose LDX and completed one CGI-S assessment Upper RTI 22 (3.7) 17 (3.7)
post-randomization. Log-rank testing was used to calculate Feeling jittery 37 (6.2) 2 (0.4)
the primary end point, and it was stratified based on 4-week Irritability 36 (6.1) 24 (5.2)
B. Acute, open-label phase of maintenance studyb
cessation status. TEAE Lisdexamfetamine
A total of 418 participants were enrolled in the open-label N (% out of 411)
phase, and 275 responders from the open-label phase entered Dry mouth 139 (33.8)
Headache 66 (16.1)
the randomized-withdrawal phase. Out of the 143 participants Insomnia 46 (11.2)
who withdrew from the open-label phase, 22 were reportedly Decreased appetite 38 (9.2)
due to adverse events, and 48 failed to meet criteria for the Nausea 35 (8.5)
Anxiety 29 (7.1)
randomized phase. Another six participants withdrew from the Constipation 28 (6.8)
LDX randomized group (none from the placebo group) due to Hyperhidrosis 23 (5.6)
adverse events. Results from the primary outcome analysis Feeling jittery 21 (5.1)
Diarrhea 21 (5.1)
indicate that the risk of relapse over 26 weeks was lower in C. 26-week double-blind, randomized controlled withdrawal phase of
those continuing LDX than those randomized to placebo, with maintenance studyc
32.1% of participants on placebo relapsing, as compared to TEAE Lisdexamfetamine Placebo
N (% out of 136) N (% out of 134)
3.7% of participants on LDX (p < 0.001) (Table 2). Nasopharyngitis 13 (9.6) 9 (6.7)
Although the results of the secondary analyses are not Headache 12 (8.8) 9 (6.7)
described in detail here, highlights from the secondary analyses Upper RTI 11 (8.1) 5 (3.7)
Dry mouth 7 (5.0) 2 (1.5)
across all available studies are suggestive of the ability of LDX to D. Open-label, 12-month extension studyd
decrease obsessive-compulsive thoughts and behavior (measured TEAE Lisdexamfetamine
by Y-BOCS-BE) and impulsive features of BED (measured by BIS- N (% out of 599)
Dry mouth 163 (27.2)
11), as well as symptom improvement (CGI-I), and that response to Headache 79 (13.2)
LDX appears as early as week 1 after treatment. McElroy and Insomnia 74 (12.4)
colleagues have provided a more thorough discussion on these Upper RTI 68 (11.4)
Nasopharyngitis 53 (8.8)
secondary outcomes and the advantages and limitations of the Nausea 41 (6.8)
selected scales in two recent publications [14,53]. Constipation 41 (6.8)
Decreased appetite 36 (6.0)
Irritability 36 (6.0)
Bruxism 35 (5.8)
Sinusitis 35 (5.8)
4.2. Safety and tolerability Feeling jittery 30 (5.0)
Anxiety 30 (5.0)
In clinical trials utilizing LDX for the treatment of BED, the
a
profile of treatment-emergent adverse events (TEAEs) was One phase II [49] and three phase III trials [50,51] were included in this
summary; all were 11–12 weeks in duration.
consistent with those seen in adults with ADHD [54–56]. b
Adverse events reported during the 12-week open-label phase preceding the
Approximately 80–85% of participants taking LDX experienced 26-week, double-blind randomized withdrawal period of the maintenance
any adverse event, but dropouts due to TEAEs in participants study [52].
c
Adverse events reported during the 26-week, double-blind, randomized with-
on LDX were relatively low in all trials (<10% of participants). drawal phase of the maintenance study.
d
Table 3 provides a list of common adverse events (occurring in Adverse events reported during the 12-month extension [57] study, in which
≥5% of participants receiving LDX) reported in the LDX for participants were recruited from previously described double-blind rando-
mized controlled trials [49,50].
BED clinical trials [49–52,57]. They are stratified by study type: N: number of participants, RTI: respiratory tract infection, TEAE: Treatment-
acute (3A) and maintenance (3C) double-blind randomized emergent adverse event.
controlled trials, and open-label study phases (3B and 3D).
When appropriate, pooled values were reported with TEAE
data from all participants who completed the safety analysis phase II and phase III studies: 343 and 344 [57]. The primary
and were receiving LDX (either open-label or blinded), and objectives of this study were to assess occurrence of TEAEs and
dividing the total number of participants reporting the side positive responses on the C-SSRS. The study consisted of a 4-
effect by the total number of participants taking LDX. A similar week dose optimization phase that was the same as in trials
calculation was used for patients receiving placebo [49–51]. 343 and 344, followed by a 48-week maintenance phase.
Long-term safety and tolerability of LDX for BED was Inclusion criteria required no clinically significant TEAEs during
assessed through an open-label extension trial that was con- participation in the previous qualifying trial, and otherwise had
ducted by recruiting participants from the previously discussed to meet inclusion criteria for the studies 343 and 344. If the

participants were enrolled 30 or more days after they com-
pleted the previous study, they could be excluded if they
started a lipid-lowering medication <3 months before screen-
ing. Measures of safety and tolerability included TEAEs, vital
signs, weight changes, ECGs, laboratory evaluations, and
C-SSRS scores. When changes from baseline were described,
baseline was set as the prior study baseline, or the extension
study screening visit (if enrolled > 30 days from previous study).
Out of the 604 enrolled, 599 were included in the safety
analysis, and 61% completed the study (369 participants). Over
the course of the study 9% (54 participants) left due to
adverse events, but only 0.5% left due to lack of efficacy (3).
The majority of participants were maintained at the 70 mg/day
dose (64.9%, 389 participants), and average length (SD) of
drug exposure was 284.3 (118.84) days. Serious TEAEs deter-
mined to be due to study drug included (one instance of each
in the same participant upon taking 100 mg LDX the day of
the event) were acute coronary syndrome and supraventricu-
lar tachycardia. Severe TEAEs considered related to study drug
were irritability (3), dry mouth (2), and insomnia (2).
The LDX product label includes a boxed warning for abuse
potential [15], although animal studies suggest LDX may have
less reinforcing effects than immediate release d-amphetamine
[58]. This was supported in a 2009 human study, with a pla-
cebo-controlled, double-blind, randomized crossover design,
that compared the abuse potential of single doses of oral
d-amphetamine (40 mg), LDX (50, 100, and 150 mg), and
diethylpropion (200mg) to placebo in 36 participants with a
history of stimulant abuse [59]. The primary measure in this
study was change on the Liking Scale of the Drug Rating
Questionnaire-Subject from stimulant to placebo, and this mea-
sure was significant for d-amphetamine and diethylpropion, but
was insignificant for all doses of LDX except 150 mg, which is
equivalent to 50% more amphetamine product as compared to
d-amphetamine 40 mg [59]. Jasinski et al. also compared abuse
potential of intravenous d-amphetamine (20 mg) or LDX (25 or
50 mg) to intravenous placebo in a randomized, double-blind,
crossover study of adult stimulant abusers [60]. The authors
found that abuse liability did not change significantly for LDX
when compared to placebo at either dose, but that it did for
d-amphetamine. As attempting to change the pharmacokinetic
profile could impact its abuse potential, Ermer et al. also com-
pared intranasal and oral pharmacokinetics of 50 mg LDX in
healthy adult men, and found no significant differences in LDX
or d-amphetamine with respect to maximum concentration,
time to maximum concentration, or absorption [61].
It is important to note that conflicting results in abuse liability
have been reported in a recent sample of 24 healthy adults
administered placebo, and equivalent concentrations of amphe-
tamine base as d-amphetamine (40 mg) and LDX (100mg) in a
double-blind, placebo-controlled, randomized crossover study
[62]. Although pharmacokinetic differences were observed as
anticipated (e.g. delayed time to maximum concentration of
d-amphetamine with LDX, but similar d-amphetamine AUC),
Visual Analog Scale measures of abuse liability (drug liking,
well-being, and more) were not different between d-ampheta-
mine and LDX when compared to placebo [62].
The clinical studies on the efficacy of LDX for the treatment
of BED discussed here excluded patients with a history of
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 235
substance abuse, although one participant in the 52-week
clinical trial discontinued the study due to periodic drug crav-
ings [57]. There was also a death in the phase II trial consistent
with methamphetamine overdose in a participant who denied
a history substance abuse during the screening [49].
Additional warnings and precautions from the product
label include (1) serious cardiovascular reactions such as sud-
den death, stroke, and myocardial infarctions, and recom-
mends avoiding use in patients with serious heart problems;
(2) blood pressure and heart rate increases; and (3) psychiatric
adverse reactions that include exacerbating preexisting psy-
chosis and potentiating new psychotic or manic symptoms.
Serious adverse events involving these drug warnings were
rare in clinical trials of LDX for BED, except for increased heart
rate and blood pressure that was observed in 5–10 percent of
patients taking LDX in these clinical trials. When described in
the 12-month safety study, the authors noted that <5% of
participants had changes in blood pressure or pulse that
were clinically significant [57].
When the investigators of the safety study presented
change in blood pressure and pulse graphically over the year
and to the week of follow-up visit, it is observable that pulse
increase occurred within the first week of therapy and roughly
plateaued by week 8. The authors report that heart rate
peaked with an increase of 8.85 (SD 10.24) beats per minute
on week 28. Heart rate elevation above baseline dropped to
approximately 5 bpm at the 1-week posttreatment follow-up
visit. Blood pressure increased slowly from baseline to a peak
increase of 2.78 (SD 10.56) mm Hg systolic (week 28) and 2.09
(SD 8.215) mm Hg diastolic (week 16) over baseline, but also
followed the same approximate pattern of plateauing at week
8. At the follow-up visit 1-week posttreatment, blood pressure
had returned to approximately baseline. In comparison, the
results of the two large, placebo-controlled randomized phase
III trials noted an increase in blood pressure of 0.2–1.45 mm
Hg (systolic) and 1.06–1.83 mm Hg (diastolic), and a heart rate
increase of 4.41–6.31 bpm after 12 weeks of treatment [50].
Finally, weight loss is a known side effect of LDX treatment
that may be considered beneficial in this population, but
should be carefully monitored because the safety of LDX for
weight loss has not been established, and past use of sym-
pathomimetic agents for weight loss has resulted in serious
adverse cardiovascular side effects [15]. When weight loss was
monitored as a safety outcome in the phase III studies 343 and
344, it was found to be significantly higher than weight loss in
patients taking placebo [50]. In the extension study, weight
loss peaked at week 44, with an average loss (SD) of 8.21 kg
(7.73), corresponding to a percent decrease in body weight
(SD) of 8.67% (7.848).
5. Regulatory issues
As discussed, LDX has been approved for the treatment of BED
in adults in the United States based on the results of the phase
II and two phase III 11–12-week studies that described the
efficacy and safety of LDX for this indication [49,50]. LDX has
also been approved in Canada for the treatment of BED [63],
as well as in Israel [64]. Other agents are being commercially
236 K. WARD AND L. CITROME
developed for the management of BED, including dasotraline,
currently in Phase III (NCT03107026).
6. Conclusions
LDX is a CNS stimulant, and the first drug with FDA approval
to treat BED. It is transformed from an inactive pro-drug to
d-amphetamine by enzymes in red blood cells [17,18]. The
mechanism of action for the treatment of BED is likely related
to increased concentrations of dopamine, norepinephrine, and
to a lesser extent, serotonin, in the synapse after d-ampheta-
mine binds to monoamine transporters [21]. LDX is only avail-
able in oral formulations, allows for once-daily dosing, and
needs to be dose-adjusted in settings of renal dysfunction
[15]. The primary study outcomes for five out of six phase II
and III clinical studies support the ability of LDX, at doses of 50
and 70 mg/day, to decrease the number of BE days per week
in adult patients with moderate to severe BED [49,50,52,57].
Secondary outcome analyses from these efficacy studies sug-
gest that LDX may also improve obsessive-compulsive, and
impulsive, aspects of BED in a time frame shorter than
11–12 weeks [14]. An additional phase III trial supports the
ability of LDX to decrease relapse rates over a 6-month period
when compared to placebo [52]. In clinical trials, the most
common TEAEs were dry mouth, insomnia, headache, and
decreased appetite, and are reflective of the adverse event
profile of LDX in adults with ADHD [54–56]. This pattern
continued in a safety and tolerability study that was 1 year
in duration [57]. Future studies will need to assess the efficacy,
safety, and tolerability of LDX for the treatment of BED in
studies with that are more inclusive of typical BED patients
with respect to comorbid diagnoses.
7. Expert opinion
Prior to FDA approval of LDX as the first drug with an indica-
tion for the treatment of BED, SSRIs and topiramate had been
considered among the best pharmacologic treatment options
for this eating disorder [5]. The mechanism of action of LDX is
unique when compared to these agents, and may represent a
more direct approach to balancing the underlying neuro-
chemical abnormalities in patients with BED. A currently
recruiting study aims to measure brain activation following
food cues in BED patients, before and after receiving 12 weeks
LDX treatment that may better characterize the effects of LDX
on BED (Table 2). Unlike antidepressants and topiramate, LDX
also has the added benefit of not contributing to weight gain
(that can be seen with antidepressants) or cognitive impair-
ment (that can be associated with the use of topiramate). A
potential downside of LDX therapy is acquisition cost, as it is
still available only as a branded product, while topiramate and
many of the SSRIs are available as generic products.
Nonetheless, a recent study comparing 12 weeks LDX treat-
ment to placebo suggests that LDX provides cost-effective
improvements in quality-adjusted life years [65].
To interpret the clinical utility of LDX treatment, Citrome
completed a review on the use of LDX for BED that included
calculating the number needed to treat (NNT) and number
needed to harm (NNH) when comparing LDX to placebo [66].
NNT and NNH are measures of effect size and indicate how
many patients would need to be treated with one agent
instead of the comparator to encounter one additional out-
come of interest. Using data pooled from three available
studies, NNT was calculated for the dichotomized CGI-I score
of improved (scores 1 and 2) versus not improved (3–7).
Highlights from this analysis include a NNT (95% CI) of 4 (4–
6) for doses of 30–70 mg/day to result in one more person
meeting CGI-I improvement as compared to placebo. When
calculated for only the phase III trials (50 and 70 mg/day LDX
doses), the effect size is more robust: 3 (3–4). NNH (95% CI)
calculations of the most common potential adverse events
include: 4 (3–5), 11 (8–17), 11 (8–17), and 19 (11–75) for dry
mouth, decreased appetite, insomnia, and headache, respec-
tively [66]. In addition, results from the 26-week maintenance
study evidenced lower rates of relapse for LDX than for pla-
cebo, 3.7% versus 32.1% [44], for a NNT of 4 (95% CI 3–6).
Ultimately, clinicians will need to weigh the efficacy of LDX for
improving BED outcomes against the potential for adverse
events. Of note, adverse events may differ in terms of impact,
and may not be clinically relevant if the adverse event is mild,
time-limited, or easily managed. For example, the average
pulse rate and blood pressure increases noted in the
described studies can be more clinically significant in patients
with hypertension or congestive heart failure. A caveat is that
patients carry variable propensities to experience different
adverse events or to achieve a therapeutic response.
As mentioned previously, there are a large percentage of
BED patients with comorbid psychiatric diagnoses [3] and
metabolic syndrome [67–70]. Physician willingness to pre-
scribe LDX for the treatment of BED will likely be impacted
by concern over the lack of safety studies in BED patient
populations with controlled comorbid psychiatric (including
substance use disorders) or CVD. More inclusive clinical trials
comparing the efficacy and safety of LDX in BED treatment
will be important for making study results more general-
izable. Additional studies comparing current treatments
used for BED, and if LDX provides added benefit to CBT in
BED treatment, will help providers determine the best treat-
ment options for their patients.
Funding
This paper was not funded
Declaration of Interest
L Citrome has engaged in collaborative research with, or received con-
sulting fees from Acadia, Alexza, Alkermes, Allergan, AstraZeneca, Avanir,
Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech,
Intra-Cellular Therapeutics, Janssen, Jazz, Lundbeck, Merck, Medivation,
Mylan, Neurocrine, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser,
Reviva, Shire, Sunovion, Takeda, Teva, Valeant, and Vanda. The authors
have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed. A reviewer on this manuscript has disclosed receiv-
ing grants/research support, consulting fees and/or honoraria within the
last three years from Angelini, AOP Orphan Pharmaceuticals AG,
AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm,
Pfizer, Pierre Fabre, Schwabe and Servier.

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