Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine’s distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed.
Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (C max), extended time to C max (T max) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.
Lisdexamfetamine dimesylate (LDX) and d-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and d-amphetamine dialyzability was also examined.
Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: randomized-withdrawal study design
- Journal of the American Academy of Child and Adolescent Psychiatry
- Published almost 6 years ago
In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design.
Lisdexamfetamine Dimesylate for Adults with Moderate to Severe Binge Eating Disorder: Results of Two Pivotal Phase 3 Randomized Controlled Trials
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- Published over 4 years ago
The efficacy and safety of lisdexamfetamine dimesylate (LDX) versus placebo in binge eating disorder (BED) was evaluated in two multicenter, double-blind, placebo-controlled trials. Adults (study 1, n=383; study 2, n=390) meeting DSM-IV-TR BED criteria were randomized (1:1) to placebo or LDX (50 or 70 mg/d) dose titration; optimized doses were maintained to the end of double-blind treatment (week 12/early termination). Change from baseline in binge eating days/week at weeks 11-12 (primary efficacy endpoint) was assessed with mixed-effects models for repeated measures. Secondary endpoints related to binge eating and medical parameters, safety, and treatment compliance were also assessed. Least squares mean (95% CI) treatment differences for change from baseline binge eating days/week at weeks 11-12 significantly favored LDX (study 1: -1.35 [-1.70, -1.01]; study 2: -1.66 [-2.04, -1.28]; both P<0.001). In both studies, treatment-emergent adverse events (TEAEs) reported by ≥10% of LDX participants were dry mouth, insomnia, and headache. Serious TEAEs occurred in 2 (1.1%) placebo participants in each study and in 3 (1.6%) and 1 (0.6%) LDX participants in study 1 and study 2, respectively. Across studies, mean increases from baseline at week 12/early termination with LDX for pulse and systolic and diastolic blood pressure ranged from 4.41-6.31 bpm and 0.2-1.45 and 1.06-1.83 mm Hg, respectively. LDX (50 and 70 mg/d) was superior to placebo in decreasing binge eating days/week from baseline and improving binge eating related key secondary endpoints. Safety results appear consistent with the known safety profile of LDX.Neuropsychopharmacology accepted article preview online, 07 September 2015. doi:10.1038/npp.2015.275.
Among young people up to 18 years of age, approximately 5 % have attention deficit hyperactivity disorder (ADHD), many of whom have symptoms persisting into adulthood. ADHD is associated with increased risk of co-morbid psychiatric disorders, including substance misuse. Many will be prescribed medication, namely methylphenidate, atomoxetine, dexamphetamine and lisdexamfetamine. If so, it is important to know if interactions exist and if they are potentially toxic.
This study examined the time course of efficacy-related endpoints for lisdexamfetamine dimesylate (LDX) versus placebo in adults with protocol-defined moderate to severe binge eating disorder (BED).
The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder.
Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score ≥28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95 % confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95 % CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score.
Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder
- European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
- Published over 4 years ago
The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD symptoms upon medication discontinuation. The objective of this narrative review and analysis was to better understand the relapse of ADHD symptoms upon discontinuation of medication treatment in children, adolescents, and adults with ADHD who have responded to medication treatment and to explore differences among different medications in maintaining treatment response. Randomized withdrawal studies of dexmethylphenidate hydrochloride (d-MPH), methylphenidate modified-release (MPH-LA), lisdexamphetamine dimesylate (LDX), guanfacine extended-release (GXR), and atomoxetine (ATX) in both children/adolescents and adults with ADHD were reviewed. The percentage of relapse was significantly higher and the time-to-relapse significantly shorter with placebo compared to active treatment in patients who were previously stable on 5 weeks to 1 year of active treatment, suggesting clinically significant benefit with continued long-term pharmacotherapy. However, percentage of relapse at each time point studied after discontinuing stimulants and GXR appears substantially higher than observed when discontinuing ATX, suggesting longer maintenance of response after discontinuing ATX than after stimulants and GXR. Additionally, slope of relapse percentages over time appears to be more rapid with stimulants or GXR than with ATX. These differences in maintenance of response among ATX, GXR, and stimulants may reflect differences in mechanisms of action and persistence of the medication effect. Alternatively, they may be due to methodological differences, including study design and response/relapse definitions. Continued investigation is needed regarding factors that affect risk of symptom relapse upon discontinuation of pharmacotherapy.