Assessment of Human Abuse Potential of Dasotraline Compared To

Drug and Alcohol Dependence 159 (2016) 26–34

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Full length article

Assessment of human abuse potential of dasotraline compared to

methylphenidate and placebo in recreational stimulant users

a,∗ a a a a b,1

K.S. Koblan , S.C. Hopkins , K. Sarma , N. Gallina , F. Jin , N. Levy-Cooperman ,

b,1 a

K.A. Schoedel , A. Loebel

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA

INC Research Toronto Inc., Toronto, ON, Canada

r t i c l e i n f o a b s t r a c t

Article history: Aims: The aim of this study was to evaluate the abuse potential of dasotraline, a novel dopamine and

Received 1 June 2015

norepinephrine reuptake inhibitor with slow absorption (tmax, 10–12 h) and elimination (t1/2 = 47–77 h)

Received in revised form 6 October 2015

that is in development for the treatment of attention deﬁcit hyperactivity disorder (ADHD).

Accepted 7 October 2015

Methods: Recreational stimulant users (N = 48) who had speciﬁc experience with cocaine, and who were

Available online 3 December 2015

able to distinguish methylphenidate (60 mg) versus placebo in a qualiﬁcation session, were randomized,

in a 6-period, double-blind, crossover design, to receive single doses of dasotraline 8 mg, 16 mg, and 36 mg,

Keywords:

methylphenidate (MPH) 40 mg and 80 mg, and placebo. The primary endpoint was the Drug Liking Visual

Attention deﬁcit disorder with

hyperactivity Analog Scale (VAS) score at the time of peak effect (Emax).

ADHD Results: There were no signiﬁcant differences between the 3 doses of dasotraline and placebo on the drug

Substance abuse liking VAS at Emax, and on most secondary endpoints. Both doses of MPH had signiﬁcantly higher VAS-

Central nervous system stimulants drug liking scores at Emax relative to both placebo (P < 0.001 for all comparisons) and dasotraline 8 mg

Amphetamines (P < 0.001), 16 mg (P < 0.001) and 36 mg (P < 0.01). The increase in heart rate for MPH and dasotraline

36 mg showed a time-course that closely matched subject-rated measures such as Any Effects VAS.

Conclusions: In this study, dasotraline was found to have low potential for abuse, which may be, in part,

related to its established pharmacokinetics (PK) proﬁle, which is characterized by slow absorption and

gradual elimination.

BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction transporters (NET; norepinephrine uptake IC50 4 nM), and a

weaker inhibitor of human serotonin transporters (SERT; sero-

Drugs that increase dopamine levels may be associated with tonin uptake IC50 15 nM; Sunovion, data-on-ﬁle, 2014). In humans,

stimulant effects and abuse (e.g., cocaine and amphetamine), dasotraline has a time to maximum plasma concentration (tmax)

whereas drugs that increase 5-HT and/or NE levels are not gen- of 10–12 h, a terminal elimination half-life (t1/2) of 47–77 h, and

erally associated with recreational abuse (e.g., selective serotonin achieves steady state plasma concentration after 2 weeks of daily

reuptake inhibitors, atomoxetine). Several of the most widely pre- dosing (Koblan et al., 2015; Hopkins et al., 2015). Among drugs

scribed treatments for ADHD (e.g., methylphenidate, amphetamine with effects on dopamine neurotransmission, drugs with a slow

preparations) increase dopamine levels, and are typically asso- onset of effect typically have reduced abuse potential (Busto and

ciated with stimulant effects, increased risk of abuse (Wilens Sellers, 1986; Farré and Camí, 1991; Volkow et al., 1995; Volkow

et al., 2008), and enhanced vulnerability to abuse of other drugs and Swanson, 2003; Swanson and Volkow, 2003). In addition,

(Mannuzza et al., 2008; Dalsgaard et al., 2014). there is evidence that an increased half-life reduces the rewarding

Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetra- effects and lowers abuse liability due to sustained elevations

hydronaphthalen-1-amine] is a potent inhibitor of human in drug concentrations resulting in sustained inhibition of DA

DA transporters (DAT; dopamine uptake IC50 3 nM) and NE transporters (Swanson and Volkow, 2003; Schoedel et al., 2010).

Dasotraline is being developed to evaluate its use in treating

the symptoms of attention-deﬁcit/hyperactivity disorder (ADHD;

American Psychiatric Association, 2013). A 4-week, ﬁxed-dose,

∗

Corresponding author at: Sunovion Pharmaceuticals Inc., 84 Waterford Drive,

placebo-controlled trial supported dasotraline as an efﬁcacious

Marlborough, MA 01752, USA. Tel.: +1 5087874356.

treatment option for adults with ADHD (Koblan et al., 2015). Thus,

E-mail address: [email protected] (K.S. Koblan).

Currently at Altreos Research Partners, Toronto, ON, Canada. the pharmacokinetic and pharmacodynamic characteristics of

http://dx.doi.org/10.1016/j.drugalcdep.2015.10.029

K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34 27

dasotraline suggest that its therapeutic effects in the treatment of orange opaque hard gelatin capsules. Based on the long t1/2 of daso-

ADHD, with sustained inhibition of DA and NE reuptake, may be traline (47–77 h), the minimum washout period between doses in

associated with lower abuse potential than methylphenidate. the treatment phase was 21 days.

The primary aim of the current study was to evaluate the abuse

potential of dasotraline compared to placebo and methylphenidate 2.3. Study phases

in recreational stimulant users. Peak Drug Liking VAS (“at this

moment”) was selected as the primary endpoint since it is the 2.3.1. Qualiﬁcation phase. To conﬁrm eligibility for the treatment

standard measure of abuse in human abuse liability studies. (Food phase of the study, subjects ﬁrst completed a randomized, 4-day,

and Drug Administration, 2010, 2013). double-blind, crossover qualiﬁcation phase, in which they received

single oral doses of immediate-release methylphenidate (60 mg)

or matching placebo, separated by a 24 h washout. A subject was

2. Methods

eligible for the treatment phase only if the following eligibility crite-

ria were met in the qualiﬁcation phase: (1) their peak score on

2.1. Design and subjects

the Drug Liking Visual Analog Scale (VAS) was 10-points higher

in response to methylphenidate versus placebo response; placebo

This was a randomized, double-blind, double-dummy, 6-way

response was required to be in the range of 45 to 55 on the Drug

crossover study in healthy recreational stimulant users in which

Liking VAS (so that subjects neither endorsed liking nor disliking

the abuse potential of single doses of dasotraline (8 mg, 16 mg, and

of placebo); and (2) safety data at the 60 mg dose methylphenidate

36 mg) were compared to placebo and methylphenidate (40 mg and

suggested that the subject would be able to tolerate the 80 mg dose

80 mg; positive controls).

of methylphenidate in the treatment phase.

The study was conducted at a single clinical research unit located

in Toronto, Ontario, Canada (INC Research Toronto, Inc.), was

2.3.2. Treatment phase. Subjects who met eligibility criteria based

approved by the local IRB, and was conducted in accordance with

on the results of the qualiﬁcation phase were randomized to single

ICH GCP guidelines and with the Declaration of Helsinki. All subjects

oral doses in 1 of 6 treatment sequences based on a computer-

reviewed and signed an informed consent document explaining

generated randomization schedule, according to a 6 × 6 Williams

study procedures and potential risks. Subjects were compensated

square design (Williams, 1949). Subjects received their assigned

for their participation in the study according to local guidelines.

dose, in the order speciﬁed, using a double-dummy procedure.

Healthy recreational CNS stimulant users, age 18–55 inclu-

Each treatment visit was 5 days to collect PK and pharmacody-

sive, were eligible for enrollment if they reported a history of

≥ namic measures up to 72 h postdose, with a 21-day washout period

10 lifetime experiences with CNS stimulants (e.g., amphetamines,

between each treatment visit. Subjects returned for a safety follow-

cocaine, methylphenidate), and use of a CNS stimulant within 12

up visit within 14 days after the last administration of study drug.

weeks prior to Screening, and use of cocaine within 12 months

prior to Screening. Reasons for exclusion included: an active med-

2.4. Pharmacodynamic measurements

ical condition, including clinically signiﬁcant neurological illness,

or psychiatric illness (as assessed by the Symptom Checklist-

Subjects underwent initial training and practice sessions. Visual

90-Revised [SCL-90-R]); any clinically signiﬁcant abnormality on

analog scale (VAS) measures were scored on a 0–100 scale (Food

physical examination, laboratory testing, or ECG; subjects currently

Drug Administration, 2010, 2013). The VAS for Drug Liking (at

with pending legal charges or on probation; subjects meeting DSM-

this moment), Overall Drug Liking, and Alertness/Drowsiness (“my

IV-TR criteria (American Psychiatric Association, 2000) for drug or

mental state is”) used bipolar VAS scoring, with 50 as a neutral

alcohol dependence (excluding nicotine and caffeine) or who had

score, and 0 = strong disliking (or drowsiness), and 100 = strong lik-

ever been in a substance rehabilitation program.

ing (or alertness). The VAS for Good Effects (“I can feel good drug

effects”), Bad Effects (“I can feel bad drug effects”), Any Effects

2.2. Study drug (“I can feel any drug effect”), Take Drug Again (“I would take this

drug again”), and Drug Similarity, used unipolar VAS scoring, with

Three doses of dasotraline were tested (8 mg, 16 mg, 36 mg) to 0 = deﬁnitely not, and 100 = deﬁnitely yes. Drug Similarity VASs

allow examination of the dose-response curve ranging from a high (“how similar is the drug you most recently received to [drug

therapeutic dose (8 mg) to a supra-therapeutic dose (36 mg) con- name]?”) provided an estimate of similarity between dasotraline

sistent with standard guidelines for abuse liability studies (Balster and drugs of other classes with which the subject was familiar,

and Bigelow, 2003; Food Drug Administration, 2013; Grifﬁths et al., including placebo. Subjects were asked about cocaine (including

2003; McColl and Sellers, 2006). The 40 mg and 80 mg doses of crack), caffeine, ecstasy (MDMA), D-amphetamine or metham-

methylphenidate were selected based on previous studies (Kollins phetamine, phencyclidine (PCP), codeine or morphine, heroin,

et al., 2001; Parasrampuria et al., 2007a,b) identifying these as LSD, nicotine, pseudoephedrine, THC, benzodiazepines, ketamine,

doses that produced signiﬁcant positive psychostimulant effects and about their “overall familiarity” with each drug. The 49-item

while minimizing potentially aversive effects, such as dizziness or Addiction Research Center Inventory (ARCI) was also administered

nausea, that are associated with doses >80 mg that can increase rat- (Martin et al., 1971). Four ARCI scales were used in the current

ings of negative effects and potentially confound the assessment of study: MBG (euphoria), A and BG (stimulant effects), and LSD

rewarding effects such as ratings of Drug Liking. (dysphoria). An assessment of the Subjective Drug Value (SDV)

To ensure double-dummy, double-blind administration, the was performed based on a procedure adapted from Grifﬁths et al.

capsules received at each treatment visit were identical. Each (2003); the permissible payment range was $0.25 to $50. Measures

dose consisted of 20 capsules: 18 capsules of either dasotraline were administered and data were captured electronically using

or matching placebo, and 2 capsules of either methylphenidate or computerized proprietary software (Scheduled Measurement Sys-

matching placebo. Methylphenidate was supplied as 20 mg tablets tem, INC Research Toronto, Inc.).

of immediate-release Ritalin® that were encapsulated on site into The timing of assessments were as follows: VAS scales and ARCI

AAel gel capsules; matching placebo was supplied as lactose 100 mg measures were performed pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8,

placebo tablets, also encapsulated into AAel gel capsules. Dasotra- 9, 10, 10.5, 11, 11.5, 12, 13, 14, 24, 36, 48, and 72 h post-dose (and

line (and matching placebo) was supplied as 2 mg Size #1 Swedish then repeated at the same intervals on Days 2 and 3; Drug Liking

28 K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34

VAS/ARCI were also performed at 0.5 and 1.5 h post-dose); Subjec- at Emax was ≥65, and the value following placebo administration

tive Drug Value, Overall Drug Liking VAS, and Take Drug Again VAS was 45–55, inclusive. A total of 52 subjects met these criteria, with

at 24, 48, and 72 h post-dose; and adverse events and vital signs a mean Emax Drug Liking VAS for methylphenidate of 87.3 (range,

were recorded at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 9, 10, 11, 65.0 to 100.0), and a mean Emax Drug Liking VAS for placebo of 50.8

12, 13, 14, 24, 36, 48, and 72 hours post-dose. Continuous cardiac (range, 50.0 to 55.0).

monitoring (telemetry and pulse oximetry) was performed from

pre-dose until at least 12 h post-dose.

3.2. Subjects and disposition

2.5. Pharmacokinetic assessments

Of the total of 52 subjects who met qualiﬁcation phase crite-

ria, 48 subjects entered the treatment phase, and 35 subjects

Blood samples were obtained pre-dose and 1, 2, 3, 6, 8, 10, 12, 14,

completed all treatment visits and, accordingly, comprise the

24, 36, 48, and 72 h post-dose (to maintain the double-blind, sam-

pharmacodynamic analysis population. Of the 13 subjects who

ples were obtained after all study treatments, including placebo).

discontinued prematurely, the most common reason for discon-

The plasma PK parameters included time to maximum observed

tinuation was withdrawal of consent (n = 4), followed by protocol

plasma concentration (tmax), maximum observed plasma concen-

violation, adverse event (n = 2 each), and miscellaneous other rea-

tration (Cmax), and area under the plasma concentration-time curve

sons (n = 1 each). Three subjects were discontinued during the

from zero to the last measurable concentration (AUC ). Plasma

0-last treatment phase due to positive urine drug screens (for cocaine,

concentrations for dasotraline were determined using a validated THC).

bioanalytical method via HPLC with MS/MS detection. Inter-assay

The PK analysis population consisted of 45 subjects for whom

coefﬁcient of variation ranged from 1.97 to 2.49%; lower limit of

sufﬁcient plasma observations were available. For the pharmaco-

quantitation (LLOQ) was 10 pg/mL.

dynamic population, 74.3% were male, with a mean (SD) age of

34.2 (9.7) years; all but 2 subjects were white. Mean (SD) BMI for

2.6. Safety assessments

the PK and pharmacodynamic populations were 24.8 (2.99) and

24.4 (2.89), respectively. All subjects reported stimulant use, 85.7%

Safety and tolerability were assessed by vital signs, physical

reported previous experience with cannabinoids, 48.6% with opi-

examination, clinical laboratory tests including breath alcohol test

oids, 34.3% with hallucinogens, 20.0% with CNS depressants, and

and urine drug screens at each study visit, continuous cardiac

11.4% with dissociative anesthetics.

telemetry, and monitoring of adverse events. Treatment-emergent

suicidal ideation was monitored using the Columbia Suicide Sever-

3.3. Pharmacodynamic results

ity Rating Scale (C-SSRS; Posner et al., 2011).

3.3.1. Validity of the study and study measures. Signiﬁcantly greater

2.7. Statistical methods

peak effects were observed for both doses of methylphenidate

compared to placebo on all positive, stimulant, and overall pharma-

The primary pharmacodynamic endpoint in the study was peak

codynamic measures (Tables 1 and 2), thus conﬁrming the validity

score (Emax) on Drug Liking VAS. Pharmacodynamic endpoints

of both the study population and the study measures as an assay

(Emax, Emin, time averaged under the effect curve [TA AUE]) were

for potential stimulant abuse liability. In addition, methylphenidate

analyzed using a mixed-effects model for a crossover study. The

was strongly identiﬁed as a stimulant (e.g., d-amphetamine,

model included treatment, period, sequence, and ﬁrst order car-

methamphetamine, or cocaine) and strongly identiﬁed as not

ryover effect as ﬁxed effects, baseline (pre-dose) measurement as

placebo on the Drug Similarity VAS (Fig. 1).

covariate where applicable, and subject nested within treatment

sequence as a random effect. If the carryover effect was found to

3.3.2. Peak pharmacodynamic effects (E ). The peak effects of all 3

be non-signiﬁcant at the 25% level, then the term was dropped max

doses of dasotraline were not different from placebo on the primary

from the analysis model. The residuals from the mixed-effect model

endpoint (Drug Liking VAS at E ), and on the secondary endpoint,

were investigated for normality using the Shapiro–Wilk W-test. max

Overall Drug Liking VAS at E (Table 1).

Parameters (Take Drug Again and Any Effects VAS Emax) that did max

For the 8 mg and 16 mg doses of dasotraline, peak effects were

not meet a normal distribution criterion (P ≥ 0.05) were analyzed

not different from placebo on the full range of secondary end-

non-parametrically. For non-parametric analyses, overall treat-

points, including Take Drug Again VAS, measures of stimulant

ment effect was assessed using Friedman’s test; pairwise treatment

effect (ARCI MBG, BG, and Amphetamine scales; Table 1), and other

comparisons were assessed using the Wilcoxon signed-rank test on

standard pharmacodynamic measures including Subjective Drug

the within-subject differences. The Benjamini and Hochberg pro-

Value (SDV), High VAS, Good Effects VAS, Alertness VAS, Energized

cedure was used to control for Type I error arising from multiple

VAS, and Any Effects VAS and the ARCI LSD scale (Table 2).

treatment comparisons, only for the primary endpoint (Benjamini

For the 36 mg dose of dasotraline, small but signiﬁcant differ-

and Hochberg, 1995).

ences compared with placebo were observed in peak effects on

PK parameters for dasotraline (Cmax, tmax, and AUC0-last) were

most secondary pharmacodynamic measures (Tables 1 and 2). In

calculated using non-compartmental analysis, and were summa-

a comparison with both doses of methylphenidate, signiﬁcantly

rized using descriptive statistics.

lower peak effects were observed for the 36 mg dose of dasotra-

line on the following subjective measures of positive drug effect:

3. Results

Drug Liking VAS, Overall Drug Liking VAS, Take Drug Again VAS, the

ARCI MBG and Amphetamine scales (but not the BG scale; Table 1);

3.1. Qualiﬁcation phase

and SDV, Good Effects VAS, (but not High VAS, Alertness VAS, or

Energized VAS; Table 2).

In the qualiﬁcation phase, 105 subjects entered a randomized,

4-day, double-blind, crossover qualiﬁcation phase in which they

received single oral doses of immediate-release methylphenidate 3.3.3. Time course. Fig. 2-A summarizes the time proﬁle over 72 h

(60 mg) or matching placebo. Subjects met qualiﬁcation phase eli- post-dose for the Drug Liking VAS for each of the study drugs. As can

gibility criteria if the Drug Liking VAS value for methylphenidate be seen, mean scores were higher for the 40 mg and 80 mg doses

K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34 29

Table 1

Effect of study drugs on pharmacodynamic measures: peak effects at Emax (top panel) and between-drug differences (bottom panel).

of methylphenidate compared with each of the doses of dasotra- greater peak mean Bad Effects VAS score was also observed for

line at 2–6 h post-dose. The time proﬁle for dasotraline 8 mg and the 36 mg dose of dasotraline compared to methylphenidate 40 mg

16 mg was similar to that of placebo, while after the ﬁrst 6 h, the (Table 2).

time proﬁle of dasotraline 36 mg fell below a VAS score of 50, in

the “disliking” range (Fig. 2-A). For the 36 mg dose of dasotraline, 3.4. Pharmacokinetic results

Overall Drug Liking VAS scores were lower at Emin than placebo

(P = 0.004). Mean dasotraline plasma concentrations over time following

single-dose oral administration at doses of 8 mg, 16 mg, and 36 mg

3.3.4. Subjective drug similarity estimates. Median Drug Similar- are displayed in Fig. 3. Mean PK parameters after single-dose

ity VAS scores for placebo, and for the 8 mg and 16 mg doses of administration of dasotraline are summarized in Table 3. As can

dasotraline, were all low (<10; not at all similar) when compared be seen, the increase in Cmax and AUC0-last appears to be dose-

to cocaine and to d-amphetamine/methamphetamine (Fig. 1). In proportional across the dosing range examined. The median tmax

contrast, there was a dose-related increase in VAS scores, for ranged from 10 to 12 h across the 3 doses (Table 3).

the 40 mg and 80 mg doses of methylphenidate, respectively, in

similarity ratings to cocaine (median values, 34 and 63), and to 3.4.1. Pharmacokinetic-Pharmacodynamic correlation. A correla-

d-amphetamine/methamphetamine (median values, 48 and 75). tional analysis found no correlation between Drug Liking VAS at

The 36 mg dose of dasotraline had lower VAS similarity rat- Emax and the Cmax of dasotraline (R = 0.01; P = 0.30).

ings to d-amphetamine/methamphetamine (median value, 39) and

cocaine (median value, 21) than either dose of methylphenidate 3.4.2. Possible carryover effect. Most of the pre-dose dasotraline

doses (Fig. 1). Median Drug Similarity VAS scores for each study plasma concentrations were below limit of quantiﬁcation (BLQ).

drug indicated that neither dasotraline (nor methylphenidate) Quantiﬁable pre-dose values (>400 pg/mL), possibly due to carry-

were perceived by subjects as having subjective effects similar to over from the previous dasotraline dose, were reported for a total of

phencyclidine, codeine or morphine, LSD, nicotine, THC, benzodi- 6 subjects who had received the 36 mg dose of dasotraline as their

azepines, or ketamine (data not shown). previous treatment, and 1 subject who had received the 16 mg dose

of dasotraline as their previous treatment.

3.3.5. Peak subjective negative effects. There were no signiﬁcant dif-

ferences between the 8 mg and 16 mg doses of dasotraline and 3.5. Safety

placebo in peak negative effects (Bad Effects VAS, Agitation VAS,

ARCI LSD scale). For the 36 mg dose of dasotraline compared to 3.5.1. Adverse events. The incidence of adverse events was simi-

placebo, signiﬁcant negative effects were observed on all three larly low for placebo and the 8 mg and 16 mg doses of dasotraline,

subjective pharmacodynamic measures (Table 2). A signiﬁcantly except for a higher incidence of insomnia for the 2 dasotraline

30 K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34

Table 2

Effect of study drugs on pharmacodynamic measures: peak effects at Emax (top panel) and between-drug differences (bottom panel).

Fig. 1. Median drug similarity VAS scores at 24 h post-dose. methylphenidate 40 mg 80 mg dasotraline 36 mg 16 mg 8 mg placebo .

doses (approximately 10% for both doses versus 0% for placebo moderate in severity, with the exception of one severe event that

and methylphenidate), and headache (23% on the 16 mg dose occurred in a subject taking methylphenidate 40 mg.

versus 13% on placebo; Table 4). A higher incidence of adverse One subject (male, age 29) reported suicidal ideation on the

events was observed on dasotraline 36 mg, and on the 2 doses C-SSRS scale at the 5-day follow-up visit after taking 40 mg of

of methylphenidate. The most notable difference was the pres- methylphenidate, but with no method, plan, intent, or behavior.

ence of insomnia in the dasotraline 36 mg group compared with There were no deaths during the study; three serious adverse

methylphenidate (31% vs 0%). All adverse events were mild or events occurred. One subject (male, age 22) was diagnosed with

K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34 31

Fig. 2. Time course of mean scores on the following scales: (A) Drug Liking (higher score indicates greater liking); (B) Subjective Drug Value; (C) Any Effects (higher score

indicates greater drug effect); (D) Take Drug Again (higher score indicates more likely to take drug again). methylphenidate 40 mg 80 mg dasotraline 36 mg 16 mg

8 mg placebo .

Fig. 3. Dasotraline plasma concentration over 72 hours post-dose (mean, SD; logarithmic scale) dasotraline 36 mg 16 mg 8 mg.

Table 3

Summary of single dose dasotraline PK parameters.

Dasotraline 8 mg (N = 42) Dasotraline 16 mg (N = 43) Dasotraline 36 mg (N = 39)

AUC0-last (h* ng/mL)

Mean (SD) 150 (35) 310 (62) 740 (150)

Median 140 310 730

Geometric mean (%-CV) 140 (23%) 300 (20%) 730 (21%)

Cmax (ng/mL)

Mean (SD) 2.8 (0.6) 5.7 (1.2) 14 (3.4)

Median 2.8 5.8 13

Geometric mean (%-CV) 2.8 (23%) 5.6 (22%) 13 (25%)

tmax (h)

Median 10 10 12

Minimum, Maximum 6.0, 14 6.0, 36 6.1, 24

tmax: time to peak concentration; PK: pharmacokinetic; SD: standard deviation.

AUC 0-last: area under the concentration-time curve from hour zero to last measurable concentration; Cmax: maximum observed plasma concentration; %-CV = percentage coefﬁcient of variation.

32 K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34

Table 4

Adverse events by treatment at onset (incidence ≥ 10%), n (%).

Placebo (n = 39) Dasotraline 8 mg (n = 42) Dasotraline 16 mg (n = 43) Dasotraline 36 mg (n = 39) MPH 40 mg (n = 40) MPH 80 mg (n = 39)

Any Event 23 (59) 26 (62) 27 (63) 36 (92) 33 (82) 35 (90)

Headache 5 (13) 7 (17) 10 (23) 15 (38) 6 (15) 8 (21)

Euphoric mood 6 (15) 7 (17) 8 (19) 11 (28) 13 (33) 20 (51)

Insomnia 0 (0) 4 (10) 4 (9) 12 (31) 0 (0) 0 (0)

Hypervigilance 4 (10) 2 (5) 4 (9) 8 (21) 12 (30) 8 (21)

Decreased appetite 1 (3) 0 (0) 1 (2) 9 (23) 3 (8) 8 (21)

Palpitations 0 (0) 1 (2) 1 (2) 8 (21) 3 (8) 4 (10)

Dry mouth 0 (0) 1 (2) 3 (7) 4 (10) 5 (13) 4 (10)

Nausea 1 (3) 0 (0) 1 (2) 6 (15) 4 (10) 2 (5)

Anxiety 0 (0) 1 (2) 1 (2) 5 (13) 1 (2) 4 (10)

Sinus tachycardia 2 (5) 1 (2) 0 (0) 4 (10) 5 (13) 5 (13)

Sleep disorder 0 (0) 0 (0) 3 (7) 4 (10) 0 (0) 0 (0)

Paresthesias 1 (3) 0 (0) 1 (2) 2 (5) 3 (8) 5 (13)

MPH: methylphenidate.

neuroendocrine carcinoma approximately 43 days after the last Effects VAS, Agitation VAS, ARCI LSD scale) in comparison to both

Treatment Visit (40 mg methylphenidate). One subject (male, age methylphenidate and placebo, suggesting that subjects perceived

25) was withdrawn from the study due to an episode of vasova- this dose as having aversive properties.

gal syncope during venous catheter insertion at Visit 6. One subject The validity of the current study as an assay of abuse potential

(female, age 31) was withdrawn from the study due to an 11-s run of was conﬁrmed by the signiﬁcant effects observed for both doses of

wide complex ventricular tachycardia that occurred at 11.5 h after methylphenidate compared to placebo on the primary measure,

receiving dasotraline 36 mg. The subject was asymptomatic during Drug Liking VAS, and on secondary measures indicating strong

the event, and vital signs were within normal limits. No subsequent stimulant effects. These ﬁndings were consistent with results

abnormalities were found on serial monitoring of ECG parameters for methylphenidate reported in previous studies (Heishman and

and cardiac enzymes over the next 36 h. Henningﬁeld, 1991; Stoops et al., 2005; Jasinski, 2000; Kollins et al.,

2001; Clemow and Walker, 2014).

3.5.2. Laboratory. Isolated laboratory abnormalities occurred; It should be noted that a comparison of immediate-release

there were no consistent clinically signiﬁcant treatment-related methylphenidate and extended-release formulations, such as

effects on any laboratory parameter. osmotic-release oral system (OROS) methylphenidate, has found

signiﬁcant drug liking and abuse potential for extended-release

drugs compared with placebo in subjects with a history of recre-

3.5.3. Vital signs and ECG. There were small increases in systolic

ational stimulant use (Parasrampuria et al., 2007a,b). However,

BP, diastolic BP, and heart rate with all study treatments, includ-

drug liking and positive effects were lower (occasionally at a

ing placebo, from pre-dose to 72 h post-dose. These parameters also

signiﬁcant level) for the extended-release methylphenidate for-

showed a trend increase as the dose of dasotraline increased, begin-

mulation compared with the IR formulation, especially in the

ning at about 4 h post-dose. There were no treatment-emergent

ﬁrst 1–2 h post-dose. Comparable ﬁndings have been reported in

increases in QTcF >60 ms, or QTcF durations >500 ms (subjects were

healthy volunteers (Kollins et al., 1998). Interestingly, a poor cor-

excluded at baseline if a male with QTcF >450 ms, or female with

relation has been reported between the plasma concentration of

QTcF >470 ms).

methylphenidate at a given time-point, and subjective pharma-

codynamic measures (Parasrampuria et al., 2007a,b). Data such

4. Discussion

as these have led to the hypothesis that subjective response to

methylphenidate (and other drugs of abuse) is largely determined,

In this randomized, double-blind study involving recreational

not by the absolute drug concentration, but by the rate of increase

stimulant users, no differences in peak subjective measures of drug

in plasma concentration and DAT occupancy (Volkow et al., 1995;

liking were found for dasotraline (single doses, 8–36 mg) compared

Volkow and Swanson, 2003; Swanson and Volkow, 2003; Kollins

with placebo. Peak effects for all 3 doses of dasotraline were not

et al., 1998; Spencer et al., 2012). The delayed tmax (10–12 h) of

different from placebo on the primary endpoint (Drug Liking VAS

dasotraline, and the more gradual rate of increase in plasma and

at Emax), and on the secondary endpoints, Overall Drug Liking VAS

CNS concentrations of drug, may contribute to the low drug liking

and High VAS.

and low abuse potential observed in the current study.

The 8 mg and 16 mg doses of dasotraline were indistinguishable

Drugs with short elimination half-lives have also been shown

from placebo across all pharmacodynamic measures associated

to have increased risk of abuse liability (reviewed by Busto and

with abuse potential. Furthermore, drug similarity VAS scores were

Sellers, 1986; Farré and Camí, 1991). In short half-life drugs, rapid

nearly identical to scores for placebo, indicating that recreational

reduction in plasma concentrations is associated with withdrawal

stimulant users perceived the subjective effects of these 2 doses of

effects that result in increased rates of drug administration (Quinn

dasotraline to be “not at all similar” to stimulant drugs.

et al., 1997). In comparison to the short (2–3 h) elimination half-

Differences in peak measures of pharmacodynamic effect

life of methylphenidate, the long (47–77 h) half-life of dasotraline

between dasotraline and placebo became evident at the 36 mg

avoids this PK-related rapid onset/offset effect.

dose, although the magnitude of differences were small. When

Comparable low abuse potential has also been reported for

compared with both doses of methylphenidate, peak effects for

the novel triple (DAT, NET, SERT) reuptake inhibitor, tesofensine,

the 36 mg dose were signiﬁcantly lower across the majority of

which also has a delayed tmax of approximately 6 h, and a very

subjective measures of stimulant drug effects, including Drug Lik-

long half-life (∼200 h; Schoedel et al., 2010). In a placebo- and

ing VAS, Overall Drug Liking VAS, Good Effects VAS, Take Drug

active-comparator controlled crossover study in recreational

Again VAS, the ARCI MBG and Amphetamine scales, and Subjective

stimulant users, the abuse potential of tesofensine was found to be

Drug Value. In addition, the 36 mg dose of dasotraline was asso-

similar to placebo, and to the NET reuptake inhibitor, atomoxetine,

ciated with signiﬁcantly greater negative subjective effects (Bad

K.S. Koblan et al. / Drug and Alcohol Dependence 159 (2016) 26–34 33

and signiﬁcantly lower than the 30 mg dose of d-amphetamine Author disclosures

(Schoedel et al., 2010). Dasotraline appears to have a low abuse

potential based on the results of this study that is similar to the

Role of funding source

non-CNS stimulant medications used in ADHD such as atomoxe-

tine (Heil et al., 2002; Jasinski et al., 2008), and signiﬁcantly less

The original clinical research summarized in this manuscript

than what has been consistently reported for both short-acting

was funded by Sunovion Pharmaceuticals Inc. Sunovion was

(Kollins et al., 2001; Heil et al., 2002) and long-acting formulations

involved in the design, collection, and analysis of the data. Inter-

of CNS stimulants (Parasrampuria et al., 2007a,b; Kollins et al.,

pretation of the results, and the decision to submit this manuscript

2001; Spencer et al., 2012).

for publication was made by the authors.

Meta-analyses of short-term studies of adult ADHD indicate that

treatment with the NET inhibitor atomoxetine is associated with

Contributors

notably smaller effect sizes compared to effects sizes observed for

stimulant medications (Faraone and Glatt, 2010). The results of the

KSK, SCH, AL, NL-C, and KAS designed the study. SCH, KS, NG,

current study suggest that there is a potential therapeutic role for

NL-C, and KAS participated in the conduct of the study and data

medications with a pharmacologic proﬁle that combine both DAT

collection. FJ assisted in the statistical analysis. KSK, SCH, KS, NG,

and NET inhibition, but without the abuse liability associated with

FJ, NL-C, KAS, and AL contributed to the interpretation of the data,

drugs that increase dopamine levels.

and preparation of the draft manuscript.

The 8 mg and 16 mg doses of dasotraline were generally well-

tolerated in this study, with an incidence of adverse events that was

similar to placebo, with the exception of higher rates of headache Conﬂict of interest statement

(NNH = 10 vs placebo) on the 16 mg dose, and insomnia (NNH = 10

vs placebo) on the 8 mg and 16 mg doses. There was a notable Drs. Koblan, Hopkins, Sarma, Loebel; and Ms. Gallina are

dose-related increase in adverse events at the 36 mg dose of daso- employees of Sunovion Pharmaceuticals Inc. Drs. Levy-Cooperman

traline, however, no adverse events were rated as “severe” at this and Schoedel are employees of Altreos Research Partners, which

dose. worked under contract to Sunovion Pharmaceuticals in the current

There were small dose-related increases in blood pressure and investigation. Hiren Mehta, PhD, of INC Research provided pharma-

heart rate, and isolated reports of adverse events related to vital cokinetic consultation; Bijan Chakraborty of INC Research provided

signs, ECG, and laboratory tests, but there were no consistent statistical consultation; and Edward Schweizer, MD, of Paladin

dasotraline-related effects of any clinical signiﬁcance on these Consulting Group, provided editorial assistance in the preparation

parameters. of this manuscript, under the direction of the authors. Financial

support for pharmacokinetic and statistical consultation, and for

editorial assistance, was provided by Sunovion Pharmaceuticals

4.1. Limitations

Inc.

Potential limitations of the current study concern the design

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