Lisdexamfetamine Dimesylate for Preschool Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4-5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were -1.1 (7.31) and 1.5 (6.93) mmHg and -0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was -26.1 (-32.2 to -20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean tmax and t1/2, respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6-17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.

Keywords: attention-deficit/hyperactivity disorder; clinical outcome; pharmacokinetics; preschool-aged children; safety; tolerability.

Conflict of interest statement

A.C.C. has served on advisory boards for Akili, Arbor, Cingulate, Ironshore, Neos, Neurovance, NLS, Noven, Pfizer, Purdue, Rhodes, Supernus, and Tris; has been a consultant for Arbor, Ironshore, Jazz, KemPharm, Neos, Neurovance, Rhodes, Shire, Sunovion, and Supernus; has been a speaker at Arbor, Ironshore, Neos, Pfizer, Shire, and Tris; has received research support from Aevi, Akili, Alcobra, Arbor, Eli Lilly, Forest, Ironshore, KemPharm, Lundbeck, Neos, Neurovance, Noven, Otsuka, Pearson, Pfizer, Purdue, Rhodes, Shire, Sunovion, Supernus, and Tris; and has received writing support from Arbor, Ironshore, Neos, Pfizer, Purdue, Rhodes, Shire, Sunovion, and Tris.

R.L.F. receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Aevi, Akili, Alcobra, Allergan, Amerex, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Bracket, Daiichi-Sankyo, Epharma Solutions, Forest, Genentech, Ironshore, KemPharm, Luminopia, Lundbeck, Merck, NIH, Neurim, Noven, Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Purinix, Receptor Life Sciences, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Teva, TouchPoint, Tris, and Validus.

P.M. and Y.W. are employees of Shire, a member of the Takeda group of companies, and hold Takeda stock.

J.W. was an employee of Shire, a member of the Takeda group of companies, at the time this research was conducted and holds Takeda stock; he is currently employed by Ironwood Pharmaceuticals (Boston, MA).

B.R. was an employee of Shire, a member of the Takeda group of companies, at the time this research was conducted and holds Takeda stock; she is currently employed by Yumanity Therapeutics, Inc. (Cambridge, MA).

S.H.K. has received research support and/or consulting fees from Akili Interactive, Bose, Jazz, KemPharm, Medgenics, Neos, Otsuka, Rhodes, Shire, and Sunovion.

The data reported in this report were analyzed by J.W., PhD.

Figures

FIG. 1.

Participant disposition.

FIG. 2.

Mean (SD) ADHD-RS-IV-PS total score by treatment week. ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV-PS, ADHD Rating Scale-IV Preschool version; FoTA, final on-treatment assessment; SD, standard deviation.

FIG. 3.

Individual lisdexamfetamine and d-amphetaminea plasma concentrations versus time, full pharmacokinetic subset. aThe reported 24-hour values for d-amphetamine are estimates based on the next predose value (0 hours).