Vyvanse - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Vyvanse - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: ADHD (Attention Deficit Hyperactivity Disorder), Binge Eating Disorder
Class: CNS stimulants
Form: Capsules
Ingredients: lisdexamfetamine dimesylate, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shells contain edible ink, gelatin, titanium dioxide (E171), and one or more of the following: FD and C Yellow #6 (E133), FD and C Blue #1 (E110), FD and C Red #3 (E127), FDA/E172 Black Iron Oxide, FDA/E172 Yellow Iron Oxide

Pharmaceutical Information

Drug Substance

Proper name: lisdexamfetamine dimesylate
Chemical name: (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate
Molecular formula and molecular mass: C15H25N3O•(CH4O3S)2  455.60
Structural formula:
Physicochemical properties: White to off-white powder that is highly soluble in water.

Clinical Trials

Efficacy Studies

Study demographics and trial design

Table 1 Summary of Patient Demographics for Clinical Trials in Specific Indication
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender
NRP104.301 Randomized, double-blind, placebo-controlled, parallel-group study conducted in children aged 6 to 12 years who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to fixed dose treatment groups receiving final doses of 30, 50,or 70mg of VYVANSE or placebo once daily in the morning for four weeks. n=285 9.0 years
(6 to 12)
Male: 69.1%
Female: 30.9%
NRP104.201 Double-blind, placebo- and activecontrolled, randomized, multi-dose, 3-period and 3-treatment crossover, study of children aged 6 to 12 years who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type) conducted in a laboratory classroom setting.Following a 3-week open-label dose titration with mixed salts amphetamine extended-release capsules, patients were randomized with respect to treatment sequence for the same dose of mixed salts amphetamine extended-release capsules (10, 20, or 30mg), VYVANSE (30, 50, or 70mg), or placebo once daily in the morning for one week each treatment. n=50 9.1 years
(6 to 12)
Male: 62%
Female: 38%
SPD489-305 Double-blind, randomized, placebo-controlled, parallel-group study conducted in adolescents aged 13 to 17 years who met DSM-IV criteria for ADHD. In this 4-week study, patients were randomized in a 1:1:1:1 ratio to a daily morning dose of VYVANSE (30, 50 or 70mg/day) or placebo for a double-blind stepwise forced-dose titration (3 weeks) followed by a 1-week Dose Maintenance Period. All subjects receiving VYVANSE were initiated on 30mg for the first week of treatment. Subjects assigned to the 50mg and 70mg dose groups were titrated by 20mg per week until they achieved their assigned dose. n=310 14.6 years
(13 to 17)
Male: 70.3%
Female: 29.7%
NRP104.303 Double-blind, randomized, placebo-controlled, parallel-group, forced dose titration study conducted in adults aged 18 to 55 years who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). In this 4-week forced-dose titration study, subjects were randomly assigned in a 2:2:2:1 ratio of each of the three active doses vs. placebo to a daily morning dose of VYVANSE or placebo for four weeks. All VYVANSE groups started at 30mg/day. Subjects randomized to 70mg titrated to that dose over a 2-week period; those randomized to 50mg titrated to that dose over a 1-week period; those randomized to 30mg began dosing on 30mg/day during Week 1 and remained on that dose throughout the study. n=420 35.1 years
(18 to 55)
Male: 54.3%
Female: 45.7%

Study results

Children

Table 2 Results of Study NRP104.301 in ADHD (Children Aged 6 to 12 Years)
Primary Endpoint Associated value and statistical
significance for Drug at specific
dosages
Associated value and statistical
significance for Placebo or active
control
ADHD Rating Scale (ADHD-RS) total score change from baseline at treatment endpoint for the ITT population Significant improvement in patient behavior was observed at endpoint for all active treatment groups.
LS Mean (SE)
30mg: -21.8 (1.60)
50mg: -23.4 (1.56)
70mg: -26.7 (1.54)
Comparison (placebo-adjusted difference):
LS Mean (95% CI)
-15.58 (-20.78, -10.38) p<0.0001
-17.21 (-22.33, -12.08) p<0.0001
-20.49 (-25.63, -15.36) p<0.0001
LS Mean (SE)
-6.2 (1.56)

Treatment effect: p<0.0001 (2-way ANCOVA)

Dunnett′s test

CI: Confidence Interval; SE: Standard Error; LS: Least Squares

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD Rating Scale (ADHD-RS), were observed at Week 1 and continued throughout the entire 4-week treatment period for all VYVANSE doses compared to placebo in children aged 6 to 12 years (Table 2). Parents (based on Conner′s Parent Rating Scale) reported significant improvement in behavior throughout the day at approximately 10am, 2pm, 6pm in the VYVANSE group when compared to placebo.

Table 3 Results of Study NRP104.201 in ADHD (Children Aged 6 to 12 Years)
Primary Endpoints Associated value and statistical
significance for Drug at specific
dosages
Associated value and statistical
significance for Placebo or active
control
Average of SKAMP-deportment scores across the treatment assessment day, using a mixed-effects model of analysis of variance (ANOVA) for the ITT population LS Mean (SE)
0.8 (0.1)
LS Mean (SE)
mixed salts amphetamine extended-release capsules (10mg, 20mg, and 30mg combined): 0.8 (0.1)
Placebo: 1.7 (0.1)
Difference in LS Mean (95% CI) of VYVANSE vs. placebo: -0.9 (-1.1, -0.7) Difference in LS Mean (95% CI) of mixed salts amphetamine extended-release capsules vs. placebo: -0.9 (-1.1, -0.7)
Difference in LS Mean (95% CI) of VYVANSE vs. mixed salts amphetamine extended-release capsules: -0.1 (-0.3, 0.1)

p<0.0001 (2-way ANOVA with treatment and period effects)

CI: Confidence Interval; LS: Least Squares; SE: Standard Error

A significant improvement in patient (aged 6 to 12 years) behavior, based upon the average of investigator ratings on the Swanson, Kotkin, Agler, M.Flynn and Pelham (SKAMP)-deportment scores across the eight sessions of a 12-hour treatment day (assessments conducted at 1, 2, 3, 4.5, 6, 8, 10, and 12 hours post-dose), was observed between patients who received VYVANSE compared to patients who received placebo (Table 3).

The results of the secondary efficacy measures (SKAMP-Attention, Clinical Global Impression Improvement [CGI-I], number of math problems attempted [PERMP-A] and number of math problems worked correctly [PERMP-C]) were supportive of the primary efficacy endpoint. On the CGI-I scale, both VYVANSE and mixed salts amphetamine extended-release capsules scores indicated significant improvement compared with placebo. In addition, LS means of Permanent Product Measure of Performance [PERMP] average scores for combined doses of active treatments across the treatment day were highly significant compared with placebo, with both associated with robust increases in the number of attempted and correct math problems.

Analog Classroom Study

A second double-blind, placebo-controlled, randomized, crossover design, analog classroom study was conducted in children aged 6 to 12 years (n=129) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following a 4-week open-label dose titration with VYVANSE (30, 50, 70mg), patients were randomly assigned to continue VYVANSE or placebo once daily in the morning for one week each treatment. A significant difference in patient behavior, based upon the average of investigator ratings on the Page 34 of 51 SKAMP-deportment scores at 1.5 hours post-dose (primary endpoint) and across all seven post-dose sessions of a 13-hour treatment day (assessments conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0 and 13.0 hours post-dose), was observed between patients who received VYVANSE compared to patients who received placebo.

Adolescents

Table 4 Results of Study SPD489-305 in ADHD (Adolescents Aged 13 to 17 Years)
Primary Endpoints Associated value and statistical
significance for Drug at specific dosages
Associated value and
statistical significance for
Placebo or active control
ADHD Rating Scale (ADHD-RS) total score change from baseline at treatment endpoint for the FAS population Significant improvements in ADHD symptoms were observed at endpoint for all VYVANSE doses compared to placebo. LS Mean (SE)
30mg: -18.3 (1.25)
50mg: -21.1 (1.28)
70mg: -20.7 (1.25)
Comparison (placebo-adjusted difference):
LS Mean (95% CI)
-5.5 (-9.7, -1.3) p=0.0056
-8.3 (-12.5, -4.1) p<0.0001
-7.9 (-12.1, -3.8) p<0.0001
LS Mean (SE)
-12.8 (1.25)

Treatment effect: p<0.0001 (2-way ANCOVA)

Dunnett′s test

CI: Confidence Interval; FAS: Full Analysis Set; LS: Least Squares; SE: Standard Error

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD Rating Scale (ADHD-RS), were observed at endpoint for all VYVANSE doses compared to placebo in adolescents aged 13 to 17 years (Table 4). The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results of the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscale analyses at endpoint. Consistent with the primary efficacy result, efficacy was demonstrated at endpoint and at every study visit for all three VYVANSE treatment groups. The mean ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscale scores consistently decreased from Visit 1 to Visit 4, and at every visit there was a consistently larger reduction in the subscale scores in VYVANSE treatment groups compared to placebo. At endpoint and at all study visits, the mean change from baseline in the ADHD-RS-IV subscale scores for all three VYVANSE treatment groups was statistically significantly different from placebo, representing an improvement in ADHD symptomatology compared to placebo.

The results of the secondary efficacy measure were supportive of the primary efficacy endpoint. On the CGI-I scale, VYVANSE scores indicated significant improvement compared with placebo.

Children and Adolescents

A double-blind, randomized, placebo- and active-controlled parallel-group, dose-optimization study was conducted in children and adolescents aged 6 to 17 years (total 317 subjects [Full Analysis Set population], 229 (72.2%) subjects aged 6 to 12 years and 88 (27.8%) subjects aged 13 to 17 years) who met DSM-IV criteria for ADHD; subjects previously treated with the active control who had not responded were not enrolled into the study. In this eight-week study, patients were randomized to a daily morning dose of VYVANSE (30, 50 or 70mg/day), active control (included for trial sensitivity) or placebo (1:1:1). The study consisted of 3 periods, as follows: a Screening and Washout Period (up to 42 days), a 7-week Double-blind Evaluation Period (consisting of a 4-week Dose-Optimization Period followed by a 3-week Dose-Maintenance Period), and a 1-week Washout and Follow-up Period. During the 4-week Dose Optimization Period, subjects were titrated until an optimal dose, based on TEAEs and clinical judgment, was reached.

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD Rating Scale (ADHD-RS), were observed for VYVANSE at endpoint compared to placebo (Table 5). The results of the secondary efficacy measures (CGI-I, change in CHIP-CE: PRF Achievement Domain) were supportive of the primary efficacy endpoint and statistically significantly different from placebo.

Table 5 Results of Study SPD489-325 in ADHD (Children and Adolescents Aged 6 to 17Years)
Primary Endpoints Associated value and statistical
significance for Drug at specific dosages
Associated value and
statistical significance for
Placebo or active control
ADHD Rating Scale (ADHD-RS) total score change from baseline at treatment endpoint for the FAS population Significant improvements in ADHD symptoms were observed at endpoint compared to placebo. LS Mean (SE)
-24.3 (1.16)

Comparison (placebo-adjusted difference):
LS Mean (95% CI)
-18.6 (-21.5, -15.7) p<0.001
LS Mean (SE)
-5.7 (1.13)

Treatment effect: p<0.001 (2-way ANCOVA)

CI: Confidence Interval; FAS: Full Analysis Set; LS: Least Squares; SE: Standard Error

Randomized Withdrawal Study (6 weeks double-blind randomized withdrawal in subjects following treatment with open-label VYVANSE for at least 26 weeks)

A double-blind, placebo-controlled, randomized withdrawal study was conducted in children and adolescents aged 6 to 17 years who met the diagnosis of ADHD (DSM-IV criteria). A total of 276 patients were enrolled into the study, 236 patients participated in the preceding study SPD489-325 and 40 subjects directly enrolled. A total of 262 subjects were in the open-label Full Analysis Set population, 185 (70.6%) subjects aged 6 to 12 years and 77 (29.4%) subjects aged 13 to 17 years. In order to ensure that the appropriate population was included in the randomized withdrawal period to evaluate the long-term maintenance of efficacy, subjects were treated with open-label VYVANSE for an extended period (at least 26 weeks) prior to being assessed for entry into the randomized withdrawal period. Eligible patients had to demonstrate treatment response as defined by CGI-S <3 and Total Score on the ADHD-RS ≤22. ADHD-RS Total Score is a measure of core symptoms of ADHD. Of patients that maintained open-label treatment response, 157 were randomized to ongoing treatment with the same dose of VYVANSE (n=78) or switched to placebo (n=79) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. Maintenance of efficacy was demonstrated based on the significantly lower proportion of treatment failure among VYVANSE subjects (15.8%) compared to placebo (67.5%) at endpoint of the randomized withdrawal period (see Figure 1). The endpoint measurement was defined as the last post-randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind randomized withdrawal phase. For the majority of subjects (70.3%) who were treatment failures, ADHD symptoms worsened at or before the Week 2 visit following randomization.

Figure 1 Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure (children and adolescents)

Adults

Table 6 Results of Study NRP104.303 in ADHD (Adults Aged 18 to 55 Years)
Primary Endpoints Associated value and statistical
significance for Drug at specific
dosages
Associated value and statistical
significance for Placebo or active
control
ADHD Rating Scale (ADHD-RS) total score change from baseline at treatment endpoint for the ITT population Significant improvement in ADHD symptoms was observed at endpoint for all VYVANSE doses.
LS Mean (SE)
30mg: -16.2 (1.06)
50mg: -17.4 (1.05)
70mg: -18.6 (1.03)
Comparison (placebo-adjusted difference):
LS Mean (95% CI)
-8.04 (-12.14, -3.95) p<0.0001
-9.16 (-13.25, -5.08) p<0.0001
-10.41 (-14.49, -6.33) p<0.0001
LS Mean (SE)
-8.2 (1.43)

Treatment effect: p<0.0001 (2-way ANCOVA)

Dunnett′s test

CI: Confidence Interval; LS: Least Squares; SE: Standard Error

Significant improvements in ADHD symptoms, based upon investigator ratings on the ADHD Rating Scale (ADHD-RS), were observed at Week 1 and were seen throughout the entire 4-week treatment period for all VYVANSE doses compared to placebo in adults aged 18 to 55 years (Table 6).

The results of the secondary efficacy measure were supportive of the primary efficacy endpoint. On the CGI-I scale, VYVANSE scores indicated significant improvement compared with placebo.

Adult Workplace Environment Study

A second double-blind, placebo-controlled, randomized, crossover design, multi-centered, adult workplace environment (AWE) study, a modified analog classroom study of VYVANSE to simulate a workplace environment, was conducted in adults (n=142) who met DSM-IV-TR criteria for ADHD. Following a 4-week open-label dose optimization with VYVANSE (30, 50, 70mg), patients were randomly assigned to continue VYVANSE or placebo once daily in the morning for one week each treatment. Significant improvements in patient performance, based upon the Permanent Product Measure of Performance (PERMP) scores, a skill-adjusted math test that measures attention in ADHD, were demonstrated at all post-dose time points measured between patients who received VYVANSE compared to patients who received placebo. The PERMP assessments were administered at pre-dose (-0.5 hours) and at 2, 4, 8, 10, 12, and 14 hours post-dose.

At the optimized dose strength, significant improvements based upon the PERMP-A (number of math problems attempted) score and PERMP-C (number of math problems answered correctly) scores were demonstrated at all post-dose time points measured between patients who received VYVANSE compared to patients who received placebo. Secondary measures of Adult ADHD-RS with prompts total score, hyperactivity/impulsivity subscale score, and the inattentiveness subscale score were also supportive of the primary efficacy endpoint and statistically significantly different from placebo. On the CGI-I scale, a significantly larger percentage of subjects receiving VYVANSE were improved compared to placebo during the crossover visits.

Randomized Withdrawal Study (6 weeks double-blind randomized withdrawal in subjects with documentation of open-label treatment with VYVANSE for a minimum of 6 months)

A double-blind, placebo-controlled, randomized withdrawal design study was conducted in adults aged 18 to 55 years (n=123) who met DSM-IV criteria for ADHD. At study entry, subjects must have had documentation of treatment with VYVANSE for a minimum of 6 months and had to demonstrate treatment response as defined by CGI-S ≤3 and Total Score on the ADHD-RS with adult prompts <22. ADHD-RS Total Score is a measure of core symptoms of ADHD. Subjects that maintained treatment response at Week 3 of the open-label treatment phase (n=116) were eligible to enter the double-blind randomized withdrawal phase (6 weeks duration), and received their entry dose of VYVANSE (n=56) or placebo (n=60). The efficacy for subjects maintaining treatment with VYVANSE was demonstrated by the significantly lower proportion of treatment failure (<9%) compared to subjects receiving placebo (75%) in the double-blind randomized withdrawal phase (see Figure 2). Treatment failure was defined as a ≥50% increase in the ADHD-RS with adult prompts Total Score and ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind randomized withdrawal phase.

Figure 2 Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure (adults)

Executive Function (Self-regulation) Behaviors Study in ADHD

A 10-week, double-blind, placebo-controlled study was conducted to evaluate change in executive function behaviors, key quality of life outcomes, and ADHD symptoms in adults with ADHD. The study enrolled adults aged 18 to 55 years (n=161) who met DSM-IV criteria for ADHD and had a total score of ≥65 on Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score by subject-report and a score of ≥28 using the Adult ADHD-RS with prompts at the Baseline visit. The difference in LS mean change from baseline to week 10 for subject-reported BRIEF-A GEC T-score (-11.2) was significantly better in the VYVANSE group compared with placebo (p<0.0001). Secondary efficacy measures of Adult ADHD Impact Module (AIM-A), ADHD-RS with adult prompts, CGI and the ADHD Index T-score of the Conners′ Adult ADHD Rating Scale – Observer: Short Version (CAARS-O:S) were all significantly better in the VYVANSE group compared with placebo.

Drug Abuse and Dependence Studies

In a human abuse liability study, when equivalent oral doses of 100mg lisdexamfetamine dimesylate and 40mg immediate-release d-amphetamine sulfate were administered to individuals with a history of drug abuse, lisdexamfetamine dimesylate 100mg produced subjective responses on a scale of “Drug Liking Effects” (primary endpoint) that were significantly less than d-amphetamine immediate-release 40mg. However, oral administration of 150mg lisdexamfetamine dimesylate produced increases in positive subjective responses on this scale that were statistically indistinguishable from the positive subjective responses produced by 40mg of oral immediate-release d-amphetamine and 200mg of diethylpropion.

Intravenous administration of 50mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring "Drug Liking", "Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were not significantly different from placebo. Administration of a dose of 20mg of intravenous d-amphetamine produced significant positive subjective responses on these scales.

Detailed Pharmacology

Binding assays showed that lisdexamfetamine dimesylate lacked affinity for human recombinant DAT and NET transporter sites. Lisdexamfetamine dimesylate was also tested against 62 specific receptor and enzyme sites that could potentially mediate adverse side effects. Lisdexamfetamine dimesylate did not bind significantly to any of these sites.

In pharmacodynamic studies, the effects of orally administered lisdexamfetamine dimesylate were generally comparable to d-amphetamine. These studies demonstrated that the total extent of the pharmacological effect of lisdexamfetamine dimesylate (increased locomotor activity) over time was increased while the onset of effect was delayed, compared with an equivalent dose of amphetamine sulphate. This delayed onset is consistent with gradual hydrolysis of lisdexamfetamine dimesylate to release d-amphetamine. Parenteral (IV or IN) administration of lisdexamfetamine dimesylate resulted in minimal pharmacological effect as compared to that induced by an equivalent d-amphetamine sulphate dose.

In Vitro and Animal Pharmacokinetics

Oral administration of lisdexamfetamine dimesylate in comparison to d-amphetamine sulfate demonstrated that the bioavailability (AUC) of d-amphetamine from the prodrug was approximately equivalent near therapeutic human equivalent doses (HEDs). At high doses well above the therapeutic range, however, both AUC and Cmax of d-amphetamine from lisdexamfetamine dimesylate were substantially decreased in comparison to AUC and Cmax of d-amphetamine from d-amphetamine sulfate.

Absorption of lisdexamfetamine dimesylate orally administered increased non-linearly with increasing dose. The clearance of lisdexamfetamine dimesylate was greater than that Page 42 of 51 of d-amphetamine following oral administration. When lisdexamfetamine dimesylate is administered via parenteral routes, there is delayed and gradual release of d-amphetamine with substantially attenuated peak concentrations when compared to immediate-release d-amphetamine.

Oral administration of lisdexamfetamine dimesylate demonstrated that lisdexamfetamine dimesylate was not detected in rat brain tissue. The major metabolites of lisdexamfetamine dimesylate following oral administration were glucuronidated amphetamine and amphetamine. These two moieties comprised >90% of the total metabolites in plasma after oral dosing.

Following intravenous administration, small amounts of hydroxylated lisdexamfetamine dimesylate were observed in plasma. As in the case of oral administration, the major metabolites from intravenous administration of lisdexamfetamine dimesylate were similar, glucuronidated amphetamine and amphetamine.

In vitro experiments demonstrated that incubation of lisdexamfetamine dimesylate in human hepatic microsomal suspensions resulted in no significant inhibition of a panel of CYP450 isoforms that included CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor induction of CYP1A2, CYP2B6 or CYP3A4/5 in cultured fresh human hepatocytes. Lisdexamfetamine dimesylate was stable in the presence of human microsomes and fresh human and rat hepatocytes. No metabolites of lisdexamfetamine dimesylate were observed.

In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. Although the clinical significance of this interaction is likely to be minimal, consideration should be given when medications metabolised by these pathways are administered.

Lisdexamfetamine dimesylate and d-amphetamine are not in vitro substrates for P-gp nor in vitro inhibitors of P-gp transport in monolayers and therefore are unlikely to be involved in clinical interactions with drugs transported by the P-gp pump.

Urinary excretion was the predominant route of elimination accounting for approximately 77% and 87% of the administered dose in males and females, respectively. Excretion in feces accounted for only 10.9% and 3.9% in males and females, respectively. Elimination of radioactivity in urine and feces occurred largely in the first 48 hours post-dose.

Excretion of radioactive labeled lisdexamfetamine dimesylate was evaluated in intact and bile duct cannulated rats. Lisdexamfetamine dimesylate was rapidly eliminated following oral or intravenous administration. Cumulative biliary excretion for the first 48 hours post-dose accounted for approximately 14% and 12% of the dose in male and female rats, respectively. The majority of radioactivity excreted in bile occurred within 8 hours post-dose. The AUC(last) for prodrug was similar for intact and bile duct cannulated rats with no gender differences. On the basis of these findings, bile excretion does not play a major role in lisdexamfetamine dimesylate elimination.

Toxicology

Acute Toxicity Studies

The LD50 value for lisdexamfetamine diHCl in rats was >1000mg/kg. Lisdexamfetamine diHCl has a 39.9% inherent d-amphetamine content. On the basis of this value, the LD50 value would be equivalent to either >399mg/kg of d-amphetamine or >548mg/kg d-amphetamine sulfate. Therefore, lisdexamfetamine diHCl is approximately 5-fold less lethal by the oral route than d-amphetamine sulfate (LD50 value of 96.8mg/kg).

Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

Subacute and Subchronic Toxicity Studies

In the pivotal 28-day repeat dose rat study, animals were administered lisdexamfetamine dimesylate 20, 40 or 80mg/kg/day or d-amphetamine sulfate at 16mg/kg/day. There was no mortality, no effects on hematological parameters, and only isolated changes associated with clinical chemistry values for mid- and high-dose group animals. The effects noted at the mid-dosage of lisdexamfetamine dimesylate were similar to those of an equimolar dose of d-amphetamine sulfate. No histological findings were present at any dosage of lisdexamfetamine dimesylate.

In the 6-month repeat dose rat study with a 4-week recovery period, animals were administered lisdexamfetamine dimesylate (20 and 40mg/kg/day) or d-amphetamine sulfate (8 and 16mg/kg/day). No treatment-related pathological changes were apparent, including evaluation of Ki-67 immunolabeling for potential proliferative changes in the liver. Overall there were no toxicologically significant differences between the two test articles.

In the pivotal 28-day repeat dose dog study, animals were administered lisdexamfetamine dimesylate 3, 6 and 12mg/kg/day or d-amphetamine sulfate at 2.4mg/kg/day. There was no mortality, and no effects on clinical pathology, ophthalmology, ECG, gross necropsy, and histopathology were observed. Other reported effects associated with lisdexamfetamine dimesylate administration were consistent with the known pharmacological effects of d-amphetamine. The mid-dose of lisdexamfetamine dimesylate demonstrated pharmacological effects similar to those of an equimolar dose of d-amphetamine sulfate.

Juvenile toxicity studies were performed in the rat (4, 10 and 40mg/kg/day lisdexamfetamine dimesylate) and dog (2, 5 and 12mg/kg/day). No adverse effects were observed upon nervous system development or reproductive function in the rat or on neurotoxicity or male reproductive endpoints in the dog.

Carcinogenicity Studies

Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed.

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for two years at doses of up to 30mg/kg/day in male mice, 19mg/kg/day in female mice, and 5mg/kg/day in male and female rats.

Reproduction and Teratology Studies

Lisdexamfetamine dimesylate had no apparent effect on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses up to 40 and 120mg/kg/day, respectively. These doses are approximately 3.2 and 19.2 times (child) and 6.5 and 38.9 times (adult) respectively the maximum recommended dose of 60mg/day on a mg/m2 body surface area basis. Amphetamine (d to lenantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat at doses of up to 20mg/kg/day.

A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Mutagenicity Studies

Lisdexamfetamine dimesylate was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli and S. typhimurium components of the Ames test and in the L5178Y/TK+- mouse lymphoma assay in vitro.

Non-Clinical Abuse Data

Non-clinical abuse studies indicate that lisdexamfetamine produced behavioural and subjective effects in rats and monkeys that are qualitatively similar to those of the CNS stimulant d-amphetamine, but that are delayed in onset. The rewarding effects, as determined in selfadministration studies, are lower than those of methylphenidate or cocaine, but are greater than those of modafinil or placebo.

Effects on Growth

A study was conducted in which juvenile rats received oral doses of 4, 10, or 40mg/kg/day of lisdexamfetamine from Day 7 to Day 63 of age. These doses are approximately 0.3, 0.8, and 3.2 times the maximum recommended human daily dose of 60mg on a mg/m2 basis. Dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after a four-week drug-free recovery period bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. Time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on Day 85 of age.

In a study in which juvenile dogs received lisdexamfetamine for six months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12mg/kg/day, which are approximately 0.5, 1.3, and 3.2 times the maximum recommended human daily dose of 60mg on a mg/m2 basis). This effect partially or fully reversed during a 4-week drug-free recovery period.