Efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder previously treated with amphetamines: analyses from a randomized, double-blind, multicenter, placebo-controlled titration study

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 4.4% of adults in the United States[1]. Currently, psychostimulants, both amphetamines (AMPH) and methylphenidate (MPH), are considered first-line ADHD pharmacotherapy in adults[2–4]. Clinically nonresponsive patients treated with one psychostimulant will often obtain an improved clinical response when switched to another psychostimulant class; possibly because classes may differ in mechanisms of action[5]. As reviewed by Arnold and colleagues, AMPH and MPH are reuptake inhibitors of norepinephrine and dopamine (DA)[5]. However, AMPH also stimulates neurotransmitter release from presynaptic receptors.

Moreover, it is observed in psychiatry that, when patients exhibit efficacy or tolerability concerns while on a treatment, it is not uncommon in clinical practice (e.g., depression treatment) for a patient to be switched to a different medication within the same class[6, 7]. In ADHD treatment and management, this has included switching from an immediate-release or short-acting formulation to a long-acting formulation[8, 9], or from a racemic mixture to a single enantiomer formulation (e.g., d-MPH)[10].

The AMPH class of psychostimulants comprises short- and long-acting formulations of mixed AMPH salts (MAS) and MAS extended release (MAS XR), respectively, and d-AMPH formulations, including short-acting d-AMPH and long-acting d-AMPH (d-AMPH-ER), and the prodrug lisdexamfetamine dimesylate (LDX). LDX is a long-acting prodrug stimulant indicated for ADHD treatment in children (6 to 12 years), adolescents (13 to 17 years), and adults[11]. The inactive prodrug is converted, primarily in the blood, to l-lysine and therapeutically active d-AMPH[12]. MAS XR is a once-daily beaded formulation, also indicated for ADHD treatment in children (6 to 12 years), adolescents (13 to 17 years), and adults[13]. Overall, studies have demonstrated the effectiveness and safety of LDX and MAS XR in adults with ADHD[14–18]. However, a qualitative comparison in a matched-group post hoc analysis suggested that LDX provided greater improvement in ADHD symptoms[16]. Unlike LDX, the pharmacokinetic profile of MAS XR is altered by gastrointestinal pH variations, as assessed by coadministration with a proton pump inhibitor that reduces stomach acid[19].

A PubMed literature search of relevant papers produced none that systematically assessed treatment response in patients switched between different formulations of the same class of stimulant (e.g., from one MPH or AMPH formulation to another). Therefore, a study assessing treatment effects of a more recent psychostimulant formulation in adults who remain symptomatic while using another psychostimulant formulation may be useful to clinicians choosing between treatment options for adults with ADHD.

The objectives of these post hoc analyses were to assess the efficacy of LDX in adults with ADHD who remained symptomatic on AMPH therapy (various formulations) prior to enrollment vs the overall study population in a 4-week, placebo-controlled, LDX trial. Comparing symptomatic recent and prior AMPH users to the overall study population of adults with ADHD treated with LDX can aid clinicians in determining if LDX may be a viable treatment option after another AMPH medication has been used with suboptimal treatment response.

In these post hoc analyses, adults with significant baseline ADHD symptoms in the prior AMPH group, despite adequate mean AMPH treatment dose and duration of prior treatment (only 1 participant was treated for <4 weeks), showed improvements in symptoms with LDX treatment similar to the overall study population. Improvement in ADHD symptoms in LDX-treated adults was similar in the prior AMPH subgroup and overall efficacy population. Moreover, global severity at baseline and global symptom improvement with LDX treatment were comparable across all treatment groups in the prior AMPH subgroup and overall efficacy population.

One study suggests that, although psychostimulants (both AMPH and MPH) are effective in ADHD management, some participants responded better to one type of psychostimulant than to the other[28]. However, results of studies that assess treatment response after switching between agents in the same class are few. A comparative review of psychostimulants suggests that many studies assessing differences between psychostimulants do not show comparisons at the individual participant level[5]. Thus, it is unknown if patient variability in terms of prior treatment history may affect response to current treatment.

This study suggests a differential response to various ADHD formulations within the same class of psychostimulants may occur, as indicated by the improved clinical response with LDX treatment in participants who had significant ADHD symptoms despite prior AMPH therapy. Although conducted in animals with results that may not apply to humans, a study by Joyce et al supports this contention; potential variability in response based on formulation differences among the same AMPH class of psychostimulants was suggested by differential response in AMPH-evoked DA release with MAS (racemic mixture of 76% d-AMPH and 24% l-AMPH salts), d-AMPH, and d, l-AMPH in the rat striatum[29].

Such variations in neurotransmitter release based on the differing formulations of the same class of psychostimulant may play a pivotal role in intrapatient variability to treatment response. LDX, which is a prodrug of d-AMPH covalently bound to therapeutically inactive l-lysine, has demonstrated consistent and low inter-and intrapatient pharmacokinetic variability in d-AMPH mean observed maximum drug concentration and area under the concentration-time curve from time zero to infinity_, as well as consistent delivery of d-AMPH in adults[30]. Although a small amount of LDX is hydrolyzed to d-AMPH in the gastrointestinal tract, the conversion into active d-AMPH occurs primarily in the blood. The LDX conversion to d- AMPH is unlikely to be affected by gastrointestinal pH and variations in normal gastrointestinal transit times[31, 32].

Another open-label, adult study that assessed LDX and MAS XR pharmacokinetics, alone or in combination with omeprazole (proton pump inhibitor) demonstrated that MAS XR-treated participants on omeprazole experienced a shortened time to maximum drug concentration (T_max) of ≥1 hour in more than 50% of participants vs MAS-XR alone. However, LDX combination therapy with omeprazole resulted in shortened T_max in only 25% of participants vs LDX alone[19]. Moreover, the study indicated that the distribution around the median d-AMPH T_max for LDX was unaffected by omeprazole administration, although for MAS XR the dispersion was compressed. These aforementioned study data suggest a variable pharmacokinetic response even among the same class of psychostimulants. Data in animal models suggest that amphetamine formulations may differ in their pharmacodynamic effects as well. In rats administered equivalent doses of LDX and d-AMPH, increases in striatal dopamine release and in locomotor activity were lower in peak effect but more sustained with LDX vs d-AMPH[33].

A post hoc comparative qualitative analysis, using groups that were matched based on treatment duration, baseline ADHD symptom severity, and approximately equivalent AMPH doses of LDX and MAS XR in adults with ADHD from 2 similar short-term trials, found that both psychostimulants demonstrated efficacy vs placebo. Safety profiles were consistent with psychostimulant use[16]. However, this qualitative analysis also suggested that LDX treatment vs MAS XR demonstrated greater numerical improvements in ADHD core and global symptoms, as well as decreased frequency of percent differences (active treatment minus placebo) in AEs. Although exploratory in nature, these data suggest that there may be within-class efficacy and safety differences among psychostimulants; however, prospective and quantitative head-to-head comparison trials are needed to confirm these findings.

Findings from clinical trials have not provided clinicians with sufficient comparative data to adequately assess which psychostimulant may be optimal for individual patients, especially since large variations in response rates to drugs and doses exist, and the best sequence of dispensing the various psychostimulant treatments by the clinician is currently unknown[34]. Studies such as the present analysis may prove beneficial to clinicians in determining appropriate treatment options after nonresponse or suboptimal response to a particular psychostimulant therapy.

Overall, the safety profile of LDX was consistent with other long-acting psychostimulants. The frequency of common TEAEs ≥5% appeared to be lower in the LDX-treated prior AMPH groups compared with the overall population, perhaps because these patients were acclimated to the effects of psychostimulant medications. This effect was also seen in a pediatric study of LDX with patient groups that were previously treated with psychostimulants[35].

Limitations of this analysis include results that may not be representative of large cohorts because of the small subgroup sample sizes and the study design features discussed below. Since analyses were not designed or powered to assess group differences and were described with summary statistics, prospective studies are needed to confirm these results. The majority of participants were non-Hispanic/non-Latino, white, and moderately to markedly ill at baseline; results may not be able to be generalized to other ethnicities, races, or global illness severity levels. Due to the post hoc nature of this analysis, factors related to prior use of AMPH were not controlled or assessed in the study: despite the knowledge that adequate mean doses of prior AMPH were used, there was no information to determine if these doses were clinically optimized; data on the level of compliance with prior AMPH treatment were also lacking; and individuals with poor tolerability to AMPH would be ineligible to participate in this study, presenting another study limitation. The baseline symptom severity before AMPH treatment was unspecified. In addition, there was no apparent limitation on study enrollment that would exclude participants with sufficient clinical response to prior medication, since symptomatic nonremitters on prior AMPH were not defined by overall clinical response to AMPH, but only by the participant’s screening ADHD-RS-IV total score.

Overall, the analyses provide a signal suggesting that, for patients who are not optimally treated with AMPH formulations, LDX remains a potential alternative to consider for the treatment of ADHD in adults. In addition, efficacy outcomes in the prior AMPH subgroup population were consistent with those of the overall study population. The LDX safety profile was consistent with long-acting psychostimulant use. However, this study was not designed to address or compare relative advantages and disadvantages of particular pharmacotherapeutic alternatives. Prospective trials assessing this signal would be helpful in determining the utility of such options in clinical management of patients requiring treatment changes.

Thomas Babcock, DO, is currently an employee of Shire Pharmaceuticals LLC, where he has worked in the Medical Affairs Department since 2005. Dr Babcock graduated from the University of Osteopathic Medicine and Health Sciences (now Des Moines University) in Des Moines, Iowa, and earned his doctorate in anthropology working in Central America. Dr Babcock has authored 12 journal articles and 1 book as of January 2011.

Bryan Dirks, MD, is currently a medical director with Shire Pharmaceuticals LLC. Dr Dirks is a diplomate of the American Board of Psychiatry and Neurology in general psychiatry. He also has a master’s of science degree in epidemiology from Harvard University School of Public Health in Boston, Massachusetts, and a master’s of business administration degree from George Washington University in Washington, DC. His research publications include work in suicidology, schizophrenia, and ADHD.

Ben Adeyi, MS, ACII, is currently an employee of Shire Pharmaceuticals LLC, and has been working in the Biostatistics and Statistical Programming Department since 2008. He has worked as a senior biometrician for Merck & Co., Inc., and, prior to working in the pharmaceutical industry, he was a senior data analyst in the Nuclear Cardiology Medicine Department at Cornell University Medical College in New York, New York. Mr Adeyi was educated at Emory University in Atlanta, Georgia, and Temple University in Philadelphia, Pennsylvania. He is a charter member of the Chartered Insurance Institute of London, England, and has coauthored several abstracts and manuscripts.

Brian Scheckner, PharmD, BCPP, CMPP, is currently an employee of Shire Pharmaceuticals LLC, where he is a Director of Scientific Publications. He has worked for Shire since 2004 in the Clinical Development and Medical Affairs Department, serving in publication and medical communication roles. Dr Scheckner was educated at the University of the Sciences in Philadelphia (PharmD) and Rutgers University (BS, Pharmacy), and has licenses/certifications in pharmacy, psychiatric pharmacy, and publications planning. His membership in professional associations includes the International Society for Medical Publication Professionals (ISMPP) and the College of Psychiatric and Neurologic Pharmacists (CPNP). His research publications include work in ADHD and MDD.