(MPH) <strong>and</strong> d-amphetamine-based stimulants were demonstrated in controlled clinical trials. 2-4 Although efficacy <strong>and</strong> tolerability pr<strong>of</strong>iles <strong>of</strong> both preparations share a high degree <strong>of</strong> similarity, 2 subtle differences exist. 5 Their putative mechanisms <strong>of</strong> action differ <strong>and</strong> individuals may exhibit different responses to both stimulants, 2,5,6 suggesting an alternative formulation could be prescribed for subjects responding inadequately to one. 1 Long-acting formulations generally have similar efficacy <strong>and</strong> tolerability versus multidose immediate-release (IR) stimulants. 2,4,7,8 Once-daily dosing with long-acting formulations may enhance convenience <strong>and</strong> adherence 2,4 as well as decrease potential abuse <strong>and</strong> diversion. 4,9-12 <strong>Comparative</strong> data evaluating long-acting formulations for ADHD treatment are limited, especially in adults. Pelham <strong>and</strong> colleagues 6 evaluated relative efficacies <strong>of</strong> four formulations in children, including sustained-release MPH <strong>and</strong> d-amphetamine formulations. Another pediatric ADHD study compared efficacy <strong>and</strong> safety <strong>of</strong> lisdexamfetamine dimesylate (LDX) versus placebo with mixed amphetamine salts extended release (MAS XR) as a reference arm (eg, no direct comparison with LDX). 13 Several clinical trials 14-19 compared efficacy <strong>of</strong> different long-acting MPH formulations in children, but the authors <strong>of</strong> this article are unaware <strong>of</strong> comparative efficacy trials <strong>of</strong> stimulants in adults. Direct head-to-head trials are required for clinicians to comprehensively compare long-acting formulations, but in their absence, we can only rely on indirect, qualitative comparisons. LDX is a long-acting, amphetamine-based stimulant approved for ADHD in adults. LDX is the first prodrug stimulant. After oral ingestion, therapeutically inactive LDX is converted to llysine <strong>and</strong> active d-amphetamine, which is responsible for the therapeutic effect. The conversion <strong>of</strong> LDX into active d-amphetamine occurs primarily in the blood. The combination <strong>of</strong> l-lysine <strong>and</strong> d-amphetamine created a new chemical entity with a prodrug technology <strong>of</strong> delivery <strong>of</strong> d-amphetamine. 20 In adults, LDX demonstrated significant efficacy versus placebo in a 4-week pivotal trial, 21 <strong>and</strong> from 2–14 hours post dose in a r<strong>and</strong>omized, controlled, simulated workplace environment trial. 22 MAS XR is also a long-acting, amphetamine-based stimulant approved for ADHD in adults. 23 MAS XR is a once-daily, extended-release, single-entity amphetamine product that contains equal proportions <strong>of</strong> IR <strong>and</strong> enteric-coated delayed-release beads. 24 The capsule contains two types <strong>of</strong> drug-containing beads that were designed to give double-pulsed delivery <strong>of</strong> amphetamine to prolong release. 23 MAS XR has demonstrated efficacy with various doses versus placebo in a 4-week, r<strong>and</strong>omized trial 25 <strong>and</strong> in a laboratory school study 26 in children from 1.5–12 hours post dose. A classroom, crossover children’s study indicated that the percent coefficient <strong>of</strong> variance for T max, C max, <strong>and</strong> area under the curve-last for LDX-treated subjects was lower than those for MAS XR-treated subjects, suggesting lower intersubject variability with LDX <strong>and</strong> potentially more consistent drug delivery among subjects. 13 Both treatments demonstrated a safety pr<strong>of</strong>ile consistent with long-acting stimulant use. 4,21,27,28 <strong>Comparative</strong> <strong>Efficacy</strong> <strong>and</strong> <strong>Safety</strong> <strong>of</strong> LDX <strong>and</strong> MAS XR in Adults With ADHD LDX <strong>and</strong> MAS XR are controlled substances <strong>and</strong> carry warnings for potential abuse. Head-to-head abuse liability studies have not been conducted between the products. Oral LDX capsules contain no free d-amphetamine <strong>and</strong> are not likely affected by simple mechanical manipulation (eg, crushing <strong>and</strong> simple extraction). 29 In contrast, mechanical manipulation may be possible with beaded technology, such as MAS XR, in which active d- <strong>and</strong> l-amphetamine are contained in the capsule <strong>and</strong> can be made accessible. Oral <strong>and</strong> intravenous (IV) abuse liability studies have been conducted with LDX only, 29,30 <strong>and</strong> not with MAS XR; therefore, no definitive conclusions can be made regarding comparative abuse-related drug-liking effect between these two treatments. However, unlike IR d-amphetamine, IV LDX did not produce significant subjective abuse-related liking in adult substance abusers compared with placebo. 30 LDX (50 <strong>and</strong> 100 mg) taken orally had reduced abuse-related liking effects compared with IR d-amphetamine (40 mg equivalent amphetamine-base dose to LDX 100 mg). At higher doses <strong>of</strong> LDX (150 mg), subject abuse-related liking scores were similar between LDX <strong>and</strong> IR d-amphetamine (40 mg). 29 Absence <strong>of</strong> direct head-to-head data motivated the present post hoc analysis <strong>of</strong> matched groups that qualitatively explores the safety <strong>and</strong> efficacy <strong>of</strong> both stimulants using data from two separate clinical trials in adults. 21,25 This qualitative assessment was designed to compare the efficacy <strong>and</strong> safety pr<strong>of</strong>iles <strong>of</strong> LDX <strong>and</strong> MAS XR in a short-term, r<strong>and</strong>omized, placebo- controlled clinical trial setting. METHODS Study Designs The study designs <strong>of</strong> both clinical trials in the present analysis have been described previously. 21,25 Briefly, both were multicenter, r<strong>and</strong>omized, double-blind, placebo-controlled, parallel-group, forced-dose escalation clinical trials. At baseline, subjects were r<strong>and</strong>omized to receive stimulant (one <strong>of</strong> three dosages <strong>of</strong> LDX or MAS XR) or placebo <strong>and</strong> began a 4-week treatment period. In the LDX trial, subjects r<strong>and</strong>omized to receive active treatment (LDX 30, 50, or 70 mg/day) initiated therapy at 30 mg/day with weekly adjustment to r<strong>and</strong>omized dose. In the MAS XR clinical trial, subjects r<strong>and</strong>omized to receive active treatment (MAS XR 20, 40, or 60 mg/day) initiated therapy at 20 mg/day with weekly adjustment to their r<strong>and</strong>omized dose. Subjects Each clinical trial enrolled adults who met Diagnostic <strong>and</strong> Statistical Manual <strong>of</strong> Mental Disorders, Fourth Edition, Text Revision, 31 criteria for a primary diagnosis <strong>of</strong> ADHD. In the LDX trial, subjects were required to be 18–55 years <strong>of</strong> age, Primary Psychiatry 45 © MBL Communications Inc. September 2010
R. Lasser, B. Dirks, B. Adeyi, T. Babcock whereas in the MAS XR trial only a lower age limit <strong>of</strong> 18 years was specified. Exclusion criteria in both trials included comorbid psychiatric conditions with significant symptoms, pregnancy, seizures, tic disorders, Tourette’s syndrome, hypertension, cardiac conditions, a positive drug screen, history <strong>of</strong> substance abuse, or use <strong>of</strong> any prescription/investigational medication (except that used to treat ADHD within 30 days <strong>of</strong> screening). Each study relied on clinical diagnosis <strong>of</strong> ADHD based on a structured diagnostic interview. The LDX study had the additional requirement that a baseline severity in clinician-rated ADHD Rating Scale IV (ADHD-RS-IV) be met for entry. The present analyses included only data from a subgroup <strong>of</strong> enrolled subjects in each trial who were matched for baseline ADHD severity <strong>and</strong> r<strong>and</strong>omized to approximately equivalent doses <strong>of</strong> delivered amphetamine base content. Subjects in the MAS XR study with baseline ADHD-RS-IV total scores
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