A phase 1, randomized, double‐blind, placebo‐controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adult subjects

Abstract Aim To assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults. Methods A phase 1, double‐blind, randomized, placebo‐controlled, single‐ and multiple‐dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4‐8), 50 mg/d (Days 9‐13), 70 mg/d (Days 14‐18), or matching placebo. Pharmacokinetic parameters for lisdexamfetamine and d ‐amphetamine were estimated by noncompartmental analysis. Results Fifteen Japanese and 19 Caucasian subjects were enrolled and randomized. The lisdexamfetamine and d ‐amphetamine plasma concentration‐time curves were similar for both ethnic groups following single and multiple doses. Mean area under the concentration‐time curves for d ‐amphetamine were higher (by 11%‐15%) in Japanese than Caucasian subjects following multiple dosing of lisdexamfetamine. Mean bodyweight was 17% lower in Japanese than Caucasian subjects. Weight‐corrected means for oral clearance were similar in both ethnic groups, with no unexpected accumulation of d ‐amphetamine. Lisdexamfetamine was generally well tolerated by both ethnic groups, with no serious adverse events reported. The 10/12 Japanese and 11/16 Caucasian subjects who received lisdexamfetamine completed the study; two Japanese and three Caucasian subjects discontinued due to adverse events. Most adverse events were of mild severity. Conclusion Pharmacokinetics were generally similar for Japanese and Caucasian subjects; the minor differences observed were likely due to bodyweight differences in the two ethnic groups. Lisdexamfetamine was generally well tolerated. Adverse events were consistent with the established safety profile of lisdexamfetamine and were similar in both ethnic groups.


| INTRODUC TI ON
Lisdexamfetamine dimesylate, the first prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD), was developed to provide a consistent and extended effect, with less potential for abuse and reduced overdose toxicity. 1 Lisdexamfetamine is available for the treatment of ADHD in several countries, including the USA and Canada in children, adolescents, and adults (Vyvanse ® ; Shire LLC), and in the EU in children (Elvanse ® ; Shire LLC). 2 After oral ingestion, lisdexamfetamine (the therapeutically inactive molecule) is converted to l-lysine and therapeutically active d-amphetamine. 3 The pharmacokinetics of lisdexamfetamine has been studied in healthy subjects and patients with ADHD. 4,5 A small study examining single-dose administration of lisdexamfetamine in children with ADHD found that plasma concentrations of d-amphetamine were dose proportional with low interpatient variability. 4 Dose proportionality and predictability of pharmacokinetic properties over a range of lisdexamfetamine doses have been described in a study of healthy adults. 5 Furthermore, after a single 70 mg oral dose of lisdexamfetamine, pharmacokinetic analysis showed that it extensively metabolized to d-amphetamine and its derivatives before rapid elimination. 6 Lisdexamfetamine has been reported to have a half-life of <1 hour. 6 In a study in healthy adults, systemic exposure to d-amphetamine was around 20 times higher than that of intact lisdexamfetamine. 6 In addition, d-amphetamine or lisdexamfetamine bioavailability in healthy adults does not appear to be significantly affected by food, 7 and the pharmacokinetics of lisdexamfetamine or d-amphetamine has been found to be consistent between men and women. 8 Within 6 hours postadministration, lisdexamfetamine was completely eliminated from subjects in a phase 1 study of oral lisdexamfetamine 70 mg/d in healthy adults. 1 d-amphetamine achieved a steady state (based on minimum plasma concentration [C min ]) on Day 5; the maximum plasma concentration (C max ; mean ± standard deviation [SD]) at steady state was 90.1 ± 29.6 ng/mL. The median time to C max (T max ) for d-amphetamine was 3 hours. Lisdexamfetamine was undetectable on Day 5, while C min for d-amphetamine was recorded as 20.6 ng/mL. It was found that 95% of d-amphetamine was absent from plasma samples 48 hours after administration of the last dose on Day 7. The area under the plasma concentration-time curve (AUC) from time 0 to time infinity (AUC 0-∞ ) for d-amphetamine was 1453 ± 645.7 ng h/mL. 1 Prior pharmacological treatment had no impact on the dose-response efficacy of lisdexamfetamine (30-70 mg/d) in a 4 week, randomized, placebo-controlled, forced-dose titration study in adults with ADHD. 9 In addition, the study found an increasing effect size with increasing lisdexamfetamine dose, and a stronger dose-response effect for severe baseline hyperactive-impulsive symptom scores and lisdexamfetamine dose when compared with less severe symptom scores. 9 Furthermore, short-and long-term studies have shown lisdexamfetamine to be effective and well tolerated in the treatment of ADHD in children, [10][11][12][13][14][15] adolescents, [14][15][16] and adults. [17][18][19][20][21][22][23] The primary objective of the current study was to assess the safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate after single and multiple oral doses in healthy adults of Japanese descent. The secondary objectives were to assess these parameters in healthy adults of non-Hispanic Caucasian descent (referred to as Caucasian hereafter) and to compare the safety and pharmacokinetic profiles of Japanese and Caucasian subjects.

| Study design and methods
This was a phase 1, double-blind, randomized, placebo-controlled, single-and multiple-dose study to evaluate the safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate administered in healthy adult subjects of Japanese or Caucasian descent. 18.0-30.0 kg/m 2 inclusive and bodyweight 50 kg or more. The main exclusion criteria included are as follows: suicide risk; history of hypertension; history of seizure (other than infantile febrile seizures); any tic disorder or current diagnosis and/or family history of Tourette's syndrome; history of cardiovascular diseases; and glaucoma. Women who were pregnant were excluded from this study, but nonlactating women who were at least 90 days postpartum or nulliparous could participate. All subjects were required to comply with the applicable contraceptive requirements of the protocol.
Subjects were also required to be willing and able to consume standardized meals during the confinement period of the study. Eligibility of subjects was confirmed during the screening period (Days −28 to −2) and reconfirmed on Day −1 of treatment. Subjects were enrolled as pairs such that Caucasian subjects matched Japanese subjects based on sex, age (±10 years), and BMI (±15%).
Subjects were confined to the clinical research center during the treatment period after checking in on Day −1, when protocol-defined safety assessments were made. On Day 1, eligible subjects were randomized (4:1) to receive lisdexamfetamine 20 mg or identical placebo capsules administered orally. Subjects were randomized according to the schedule developed by PRA International through the use of a four-digit randomization number allocated prior to dosing.
Treatment assignments giving details of individual subject treatment were provided in code-break envelopes, which were held at the site by the designated unblinded pharmacist or dispenser. Placebo and lisdexamfetamine capsules were overencapsulated to ensure both treatments were similar in shape, size, weight, and color.
Subjects were discharged from the study center on Day 21 after study-related assessments were completed. A telephone follow-up was conducted 7 days (±2 days) after subjects received the last dose of lisdexamfetamine or placebo to record adverse events (AEs) and any changes in concomitant medications.

| Number of subjects (planned)
The study was designed to enroll 30 healthy male and female subjects with the intention that in each ethnic group, 12 subjects were to receive single and multiple doses of lisdexamfetamine, and 3 subjects were to receive single and multiple doses of placebo. A minimum of 12 Japanese and 12 Caucasian subjects were required to complete the study. No formal calculations were performed to determine sample size, which was based on feasibility and similar to that of comparable studies. 5,24

| Pharmacokinetic evaluation
Blood sampling for pharmacokinetic analysis was performed at prespecified time points. Plasma samples from subjects dosed with lisdexamfetamine were analyzed for lisdexamfetamine and d-amphetamine using validated liquid chromatography with tandem mass spectrometry detection methods. The method was linear over the range 1-100 ng/mL for lisdexamfetamine and 2-200 ng/mL for d-amphetamine, with lower limits of quantification of 1 ng/mL for lisdexamfetamine and 2 ng/mL for d-amphetamine. Plasma quality control samples were prepared in control human plasma at three concentration levels (3,20, and 80 ng/mL for lisdexamfetamine; and 6, 40, and 160 ng/mL for d-amphetamine), stored with the study samples, and assayed with each batch of study samples against freshly prepared calibration standards. The data for both calibration standards and quality control samples were in accordance with the US Food and Drug Administration Guidance for Industry. 25 Pharmacokinetic parameters, including C max , AUC, and apparent oral clearance (CL/F), were determined from the actual blood sampling times and plasma concentration-time data for lisdexamfetamine and d-amphetamine by noncompartmental analysis.

| Safety and tolerability assessments
Subjects were questioned about AEs at screening, each day during each treatment period and during the follow-up telephone call. AEs were recorded and classified using version 15.1 of the Medical Dictionary for Regulatory Activities, by system organ class (SOC) and preferred term, throughout the study period TA B L E 1 Demographic and baseline characteristics for Japanese and Caucasian subjects overall and by treatment group

| RE SULTS
A total of 34 healthy subjects (24 men and 10 women) were enrolled in the study and received at least one dose of investigational product. Of the 34 subjects, 15 were of Japanese descent and 19 were Caucasian. Baseline characteristics were generally similar in both ethnic groups (Table 1). However, although subjects were matched for BMI, Japanese subjects were lighter (mean weight 63.09 vs 75.46 kg) and shorter (mean height 167.10 vs 177.84 cm) than Caucasian subjects.

| Subject disposition
In the lisdexamfetamine groups, 10/12 Japanese subjects and 11/16 Caucasian subjects completed the study ( Figure 1). Two Japanese subjects randomized to receive lisdexamfetamine discontinued the study due to a mild AE (one during the single-dose period and the other during the multiple-dose period). Five Caucasian subjects in the lisdexamfetamine group discontinued from the study, three due to AEs that were mild or moderate in severity (see safety results), one due to dosing error, and one due to a protocol violation. All subjects in the placebo groups completed the study.

| Pharmacokinetics
For lisdexamfetamine (not shown) and d-amphetamine (Figure 2), the plasma concentration-time curves were generally similar in shape for Japanese and Caucasian subjects following a single-dose and at each lisdexamfetamine multiple-dose level.
Selected plasma pharmacokinetic parameters by dose and ethnic group are shown for lisdexamfetamine in Table 2 and for d-amphetamine in Table 3. Mean C max for d-amphetamine was higher (by approximately 34%) in Japanese than Caucasian subjects with single dosing (21.14 vs 15.79 ng/mL, respectively) and at each lisdexamfetamine multiple-dose level (range approximately 16%-24% higher for d-amphetamine in Japanese subjects). As a result, mean AUC values from time 0 to the time point of the dosage interval (AUC τ ) for the multiple-dose period for d-amphetamine in Japanese subjects were also generally higher (by approximately 11%-15%) than those seen in Caucasian subjects. Regression analyses of AUC τ and C max demonstrated a linear relationship between exposure to d-amphetamine and dose increase; AUC τ slope estimates were 1.07 for Japanese subjects and 1.11 for Caucasian subjects, and slope estimates for C max were 1.02 for Japanese subjects and 1.09 for Caucasian subjects.  Table 3).
The weight-corrected total or CL/F and t ½ for d-amphetamine were generally consistent across the dose range studied and were similar in both subject groups (

| Safety results
Single (    The postdose means for SBP, DBP, and pulse rate during both treatment periods were higher in the lisdexamfetamine groups than in the placebo groups, consistent with the known safety profile.
Postsingle dose means for SBP, DBP, and pulse rate were generally higher for Japanese subjects than for Caucasians (    also evident in the placebo group. However, Japanese subjects experienced a gain from baseline weight: −0.53 kg and +0.70 kg from baseline for Caucasian and Japanese subjects, respectively. There were no positive responses to any of the C-SSRS questions concerning suicidal behavior, suicidal ideation, or suicide attempts at any time point during the study.

| D ISCUSS I ON
In this study, single (20 mg) and multiple increasing doses (20, 50, and 70 mg/d) of lisdexamfetamine (a prodrug stimulant) were administered to healthy subjects of Japanese and Caucasian descent.
Lisdexamfetamine and the therapeutically active d-amphetamine exhibited plasma concentration-time curves similar in shape for Japanese and Caucasian subjects in the single-and multiple-dose periods. AE profiles were similar across the two ethnic groups, and all TEAEs were mild or moderate in severity.
The C max for d-amphetamine reported here was approximately 34% higher in Japanese than Caucasian subjects during the single-dose period, and at each lisdexamfetamine dose level in the multiple-dose period (range approximately 16%-24% higher for d-amphetamine), resulting in higher mean AUCs in Japanese than Caucasian subjects (range approximately 11%-15% higher for d-amphetamine during the multiple-dosing period). The observed differences in C max and AUC for lisdexamfetamine and d-amphetamine could potentially be due to bodyweight differences between Japanese and Caucasian subjects. On average in the lisdexamfetamine groups, Japanese subjects were approximately 17% lighter than Caucasian subjects. Weight-corrected means for CL/F were similar in Japanese and Caucasian subjects.
The AUC τ and C max for d-amphetamine behaved in a linear, dose-proportional manner across the dose range studied for both Japanese and Caucasian subjects, reinforcing previous findings. 4,5 There were no unexpected accumulations of d-amphetamine in Japanese or Caucasian subjects.
In the study reported here, lisdexamfetamine was absorbed, metabolized, and excreted in a similar manner in Japanese and Caucasian subjects. Greater mean exposure was observed in Japanese subjects, potentially also due to differences in bodyweight.
T max and t ½ of both lisdexamfetamine and d-amphetamine were similar across both groups and in accordance with a previous study in healthy adults. 5 With regard to safety, single and multiple doses of lisdexamfetamine were generally well tolerated in the current study, with both Japanese and Caucasian subjects experiencing similar, generally mild TEAEs that were resolved without therapeutic intervention. TEAEs were consistent with the established safety profile of lisdexamfetamine reported in phase 3 clinical trials. 16,17,27 In the current study, subjects from both ethnic groups had changes in SBP and DBP following exposure to lisdexamfetamine.
However, small mean changes in blood pressure and accompanying pulse rates have been previously reported in a number of other    When the dose of lisdexamfetamine was increased to 70 mg/d, the predose pulse rate appeared to be higher compared with the value at screening. This is not unexpected and has also been seen with other products containing d-amphetamine in Western populations. Lisdexamfetamine 70 mg once daily generally is associated with increased pulse rate versus baseline over the course of the day. 24 This has not previously been associated with a safety risk when used according to label instructions in Western populations, but experience in a Japanese population is more limited, which may have some clinical significance. One subject discontinued lisdexamfetamine treatment due to ECG changes. Discontinuation due to changes in ECG parameters following lisdexamfetamine treatment has been reported in a short-term, randomized, double-blind trial of patients aged 6-12. 31 However, it has been suggested that these discontinuations were impacted by variations in ECG interpretation. 32 Furthermore, an open-label prospective study of cardiovascular health in adults found no clinically meaningful changes with regards to cardiac function, physiology, or structure. 33 Therefore, the ECG changes exhibited by a single subject in this study were not considered a significant signal that departed from the known safety profile of lisdexamfetamine.
There were no serious or severe TEAEs and no new or unexpected safety findings in the study. Generally, no notable differences were observed between Japanese and Caucasian subjects.
These results must be interpreted with caution due to the small sample size and the population studied (healthy adults) as it may not accurately reflect the general population or the full spectrum of subjects with ADHD, which includes children and adolescents. An additional limitation is the short follow-up period of this study.
Overall, the data from this phase 1 study suggest that lisdexamfetamine may be administered to Japanese subjects at the same dose range as that used in Caucasian subjects, without any additional concerns relating to increased drug exposure or safety.
However, studies in larger populations of Japanese subjects with ADHD will further elucidate the safety and pharmacokinetic profile of lisdexamfetamine in this population.

ACK N OWLED G M ENTS
We would like to thank Jaideep Purkayastha for his assistance in reviewing early drafts of the manuscript. Under the direction of the authors, Fiona Boswell, an employee of Caudex, Oxford, UK, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing and fact-checking the manuscript, and coordination and collation of comments were also provided by Caudex.
Shailesh Desai from Shire also reviewed and edited the manuscript for scientific accuracy. Shire International GmbH provided funding to Caudex, Oxford, UK, for support in writing and editing this manuscript.
Although employees of Shire and Shionogi & Co., Ltd. were involved in the design, collection, analysis, interpretation, and fact-checking of information, the content of this manuscript, interpretation of the data, and decision to submit it for publication in Neuropsychopharmacology Reports was made by the authors independently. All authors take final responsibility for the decision to submit for publication and have approved the final version of the paper.

CO N FLI C T S O F I NTE R E S T
All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors are entirely responsible for the scientific content of the paper.

DATA R E P O S I TO RY
The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participant's data behind the results reported in this article, will be available 3 months after the submission of a request, to researchers who provide a methodologically sound proposal after de-identification in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.
Data listings are not publicly available for this study because consent for all data directly associated with the results to be made available in a permanent, publicly accessible data archive, or repository was not obtained in the patient consent forms.

A PPROVA L O F TH E R E S E A RCH PROTO CO L BY A N I N S TITUTI O N A L R E V I E WER B OA R D
The protocol for this research project has been approved by a suitably constituted ethics committee of the institution and it confirms to the Declaration of Helsinki. Approval was provided by Alpha IRB, San Clemente, CA.

I N FO R M ED CO N S ENT
All informed consent was obtained from the subjects and/or guardians.

R EG I S TRY A N D R EG I S TR ATI O N N U M B E R O F TH E TR I A L
Not applicable.

A N I M A L S TU D I E S
Not applicable.