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Lisdexamfetamine - an overview | ScienceDirect Topics
Chapters and Articles You might find these chapters and articles relevant to this topic. 4 Lisdexamfetamine Lisdexamfetamine is a therapeutically inactive amphetamine prodrug which, after oral ingestion is hydrolyzed on the surface of red blood cells to l -lys
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4 Lisdexamfetamine
Lisdexamfetamine is a therapeutically inactive amphetamine prodrug which, after oral ingestion is hydrolyzed on the surface of red blood cells to l-lysine and d–amphetamine. As a consequence, lisdexamfetamine has an extended duration of action with maximum plasma concentration of dexamphetamine achieved in 3.5–3.7 h (Boellner et al., 2010), and clinical effects that persist up to at least 13 h in children and 14 h in adults. The fact that this extended duration of action is a consequence of rate limiting biotransformation distinguishes lisdexamfetamine from other the long acting stimulants that depend on a range of physical delivery technologies. Since lisdexamfetamine is not bio-transformed into its active compounds any more rapidly if inhaled or injected, the risks of drug abuse are considerably reduced. Lisdexamfetamine is at least as effective a treatment of ADHD as are the long acting methylphenidate compounds and the non-stimulant atomoxetine with recent European studies suggesting it may even be more efficacious (Coghill et al., 2013; Dittmann et al., 2013). In the US lisdexamfetamine was approved by the FDA for children with ADHD in 2007, and for adults in 2008. Lisdexamfetamine is also approved for the management of ADHD in children and adults in Canada, Brazil and Australia and for children who are not optimally treated with methylphenidate in the UK and several other European countries.
4.1 ADHD- comorbidities and non-core symptoms
In children lisdexamfetamine was shown to be effective in improving emotional lability as well as core ADHD symptoms (Childress et al., 2014). The study demonstrated that the reduction of affective symptoms was not dependent on initial emotional lability intensity, and decreased in both groups of patients (ADHD with not prominent and prominent emotional lability at baseline) versus placebo. No worsening in emotional expression in children with ADHD treated with lisdexamfetamine for 7 weeks was observed in an open-label trial with Emotion and Expression Scale for Children used as primary outcome measure (Katic et al., 2012). Lisdexamfetamine improved reading rate but not accuracy on the Gray Oral Reading Test - 4 in a modified laboratory school study involving 26 children aged 6–12 (Wigal et al., 2012). Lisdexamfetamine did not improve smoking cessation rates or concomitant nicotine dependence in adults with ADHD in a small study of 32 subjects (Kollins et al., 2014).
4.2 Affective disorders
In a study that aimed to analyze the response to the stimulant in escitalopram non-remitters, adults with Major Depressive Disorder who failed to respond to an 8 week trial of escitalopram, were administered lisdexamfetamine or placebo for the period of 6 weeks. The primary endpoint assessment was the Montgomery – Asberg Depression Rating Scale (MADRS) (Trivedi et al., 2013). The results were positive with reduced depressive symptoms and an adjusted effect size of 0.3 for lisdexamfetamine. An exploratory open-label pharmacokinetic study of concomitant administration of lisdexamfetamine and venlafaxine extended release revealed no alteration of exposure to either lisdexamfetamine or venlafaxine with combined treatment. However increased blood pressure and pulse in the combined group suggests a need for more rigorous vital signs monitoring when these medications are given together (Ermer et al., 2013).
An interesting study of lisdexamfetamine in 45 adult patients with stable bipolar I/II disorder and comorbid ADHD found that lisdexamfetamine administered as add-on to the participants usual medications for four weeks had a beneficial impact on not only major metabolic parameters and body weight decrease, but also on the Self-Report Scale, MADRS and CGI scores (McIntyre et al., 2013). No subjects were discontinued due to destabilization of the bipolar disorder.
4.3 Schizophrenia
Lisdexamfetamine was administered in a 10 week open label study followed by a 4 week randomized placebo controlled withdrawal, as adjunctive therapy to outpatients treated with atypical antipsychotics with clinically stable schizophrenia and predominant negative symptoms (Lasser et al., 2013). At week 10 more than a half of participants significantly improved on both modified Scale for the Assessment of Negative Symptoms (minimum of 20% reduction), and Positive and Negative Syndrome Scale. Abrupt lisdexamfetamine discontinuation did not however result in any worsening of positive or negative symptoms.
4.4 Chronic fatigue syndrome
In adult patients with chronic fatigue syndrome, lisdexamfetamine was significantly better than placebo in improving fatigue symptoms, pain and global functioning, but did not show any benefits for emotional control, initiative, working memory, planning/organizing and task monitoring included in subscales of the adult version of the Behavior Rating Inventory of Executive Function (BRIEF)(Young, 2013).
4.5 Multiple sclerosis
The hypothesis that lisdexamfetamine may improve cognition in multiple sclerosis patients was supported in a recent phase II double – blind placebo controlled study with sixty three randomized patients (Morrow et al., 2013). Patients treated with lisdexamfetamine significantly improved on Symbol Digit Modalities Test and CVLT2. Although there was no improvement observed on other measured outcomes, including other cognitive assessments, depression and fatigue evaluation – lisdexamfetamine was shown to improve cognition and mental speed.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814002366
3.3.2.2 Lisdexamfetamine
Lisdexamfetamine (LDX) enhances dopamine and norepinephrine in the central nervous system and is used for Attention Deficit Hyperactivity Disorder (ADHD). Patients with MDD in partial or full remission were randomized to LDX 20–70 mg/d (N=71) or placebo (N=72) as an augmentation to SSRI monotherapy for nine weeks (Madhoo et al., 2014). Compared to placebo, the LDX treated patients showed no objective cognitive improvement (secondary outcome), but improved significantly on a self-report measure of executive functions (BRIEF-A) (primary outcome). The risk of bias in the study was evaluated as low (Tables 1 and 5).
URL: https://www.sciencedirect.com/science/article/pii/S0924977X16308379
Highlights
•Lisdexamfetamine (LDX) is rapidly absorbed after intact oral administration.
•The peptide transporter PEPT1 likely mediates absorption in the small intestine.
•Red blood cell peptidase(s) metabolize LDX into d-amphetamine and its metabolites.
•CYP enzymes do not metabolize LDX and LDX does not cross the blood–brain barrier.
•LDX has a blunted effect on brain dopamine function versus other stimulant drugs.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814000781
1 Introduction
Lisdexamfetamine dimesylate (LDX; Vyvanse®, Shire US Inc., Wayne, PA, USA; Elvanse®, Shire Pharmaceuticals Ltd, Chineham, Basingstoke, Hampshire, UK; Venvanse®, Shire Farmacêutica Brazil LTDA, São Paulo, SP, Brazil Fig. 1) is a pharmacologically inactive prodrug of d-amphetamine covalently linked to the amino acid l-lysine, and it is currently used for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged ≥6 years and adults (Najib, 2009; Popovic et al., 2009; Weisler et al., 2009). LDX is metabolized to d-amphetamine by a unique mechanism involving an enzymatic process predominantly associated with red blood cells. The pharmacology, toxicology, and pharmacokinetics of d-amphetamine have been extensively investigated and are relatively well understood. However, the hydrolysis of LDX appears to prevent the rapid appearance of d-amphetamine in the blood that is seen following oral (PO) or intravenous (IV) administration of other amphetamine products. The slower appearance of LDX in blood and, consequently, brain tissue suggests a pharmacokinetic profile that supports once-daily administration without the need to employ additional sustained-release technologies. Furthermore, we shall review evidence showing that the generation of d-amphetamine from the hydrolysis step appears to produce qualitative and quantitative differences between the pharmacodynamic effects of LDX and that of immediate-release d-amphetamine when compared at molar-equivalent doses. Hence, the profile of LDX in some in vivo studies is somewhat different compared with immediate-release d-amphetamine.
Fig. 1. Enzymatic conversion of lisdexamfetamine dimesylate to d-amphetamine and l-lysine by peptidase enzymes in red blood cells.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814000781
4.4 Lisdexamfetamine dimesylate
A randomized, double blind, placebo controlled trial evaluated lisdexamfetamine dimesylate, a neurostimulant, in regards to attention and working memory (Tramontana et al., 2014). Thirteen patients in the post-acute phase of moderate to severe TBI were compared with placebo. The study showed improvement in attention and working memory without clear improvements in processing speed. No other major clinical trials have been completed.
URL: https://www.sciencedirect.com/science/article/pii/S0006899316000342
4.4 Lisdexamfetamine dimesylate (LDX)
LDX is the only prodrug that has a stimulant effect on the central nervous system. It is hydrolyzed in the blood to crop long-acting d-amphetamine (Ermer et al., 2016). It increases DA and NA levels by inhibiting reuptake into the presynaptic neuron thus LDX increases the release of these monoamines into the extra neuronal space. LDX is specified for several impulse control treatments such as adult hyperactivity disorder and mild binge eating disorder. The United States Food and Drug Administration (FDA) approved LDX (Vyvanse) for treating moderate to severe BED in adults in early 2015. The efficacy and safety of LDX for treating moderate to severe BED for up to 12 months have been demonstrated in studies with its adverse effects in multi-site, double-blind, randomized, placebo-controlled clinical trials (Gasior et al., 2017; McElroy et al., 2017).
There are a few studies on pharmacotherapy for BED disease, which suggests high and rapid relapse rates. A recent study, investigated the neurobiological changes that occur with LDX treatment in adults with moderate to severe BED disease, reported that BED symptomology and neural connectivity uniquely to the effects of LDX (Griffiths et al., 2019).
URL: https://www.sciencedirect.com/science/article/pii/S0149763422002494
Abstract
Lisdexamfetamine dimesylate (LDX) is a novel pro-drug of d-amphetamine that is currently used for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years and adults. LDX is enzymatically cleaved to form d-amphetamine following contact with red blood cells, which reduces the rate of appearance and magnitude of d-amphetamine concentration in the blood and hence the brain when compared with immediate-release d-amphetamine at equimolar doses. Thus, the increase of striatal dopamine efflux and subsequent increase of locomotor activity following d-amphetamine is less prominent and slower to attain maximal effect following an equimolar dose of LDX. Furthermore, unlike d-amphetamine, the pharmacodynamic effects of LDX are independent of the route of administration underlining the requirement to be hydrolyzed by contact with red blood cells. It is conceivable that these pharmacokinetic and pharmacodynamic differences may impact the psychostimulant properties of LDX in the clinic. This article reviews the preclinical pharmacokinetics, pharmacology, and toxicology of LDX.
This article is part of the Special Issue entitled ‘CNS Stimulants’.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814000781
4.3 Schizophrenia
Lisdexamfetamine was administered in a 10 week open label study followed by a 4 week randomized placebo controlled withdrawal, as adjunctive therapy to outpatients treated with atypical antipsychotics with clinically stable schizophrenia and predominant negative symptoms (Lasser et al., 2013). At week 10 more than a half of participants significantly improved on both modified Scale for the Assessment of Negative Symptoms (minimum of 20% reduction), and Positive and Negative Syndrome Scale. Abrupt lisdexamfetamine discontinuation did not however result in any worsening of positive or negative symptoms.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814002366
4.1 ADHD- comorbidities and non-core symptoms
In children lisdexamfetamine was shown to be effective in improving emotional lability as well as core ADHD symptoms (Childress et al., 2014). The study demonstrated that the reduction of affective symptoms was not dependent on initial emotional lability intensity, and decreased in both groups of patients (ADHD with not prominent and prominent emotional lability at baseline) versus placebo. No worsening in emotional expression in children with ADHD treated with lisdexamfetamine for 7 weeks was observed in an open-label trial with Emotion and Expression Scale for Children used as primary outcome measure (Katic et al., 2012). Lisdexamfetamine improved reading rate but not accuracy on the Gray Oral Reading Test - 4 in a modified laboratory school study involving 26 children aged 6–12 (Wigal et al., 2012). Lisdexamfetamine did not improve smoking cessation rates or concomitant nicotine dependence in adults with ADHD in a small study of 32 subjects (Kollins et al., 2014).
URL: https://www.sciencedirect.com/science/article/pii/S0028390814002366
5 Summary
Lisdexamfetamine dimesylate is a novel prodrug of d-amphetamine that is rapidly absorbed intact after oral administration in animals and humans and is inactive at receptors, transporters, and enzymes in vitro. Absorption occurs via an active transport process likely mediated by the peptide transporter PEPT1, although this is still controversial. Following absorption, LDX is metabolized by peptidase(s) associated with red blood cells to release the active drug, d-amphetamine, and a naturally occurring amino acid, l-lysine. Red blood cells have a high capacity for the metabolism of LDX to d-amphetamine, and substantial hydrolysis occurs even at low hematocrit levels. LDX is not metabolized by CYP enzymes, and metabolism is restricted to the formation of d-amphetamine and its metabolites (ie, there are no metabolites of LDX itself). LDX is unlikely to be involved in drug–drug interactions mediated by CYP enzymes or by P-gp. LDX itself does not appear to cross the blood–brain barrier; all of its pharmacologic activity is ascribed to d-amphetamine. The rate of hydrolysis of LDX to amphetamine occurs with a t1/2 of ∼1–1.5 h.
From a toxicologic perspective, LDX was unremarkable, and the major findings were changes in behavioral activity typical of stimulant administration, with associated reductions in body weight gain, growth measurements, and food intake, which are expected pharmacologic responses to amphetamine. There were no histopathologic changes in any study related to LDX or d-amphetamine exposure. From a physiological and behavioral perspective, LDX shows a number of important differences from immediate-release d-amphetamine. For instance, at molar equivalent doses, d-amphetamine causes substantially larger increases in striatal dopamine efflux than does LDX and correspondingly 4-fold larger increase in locomotor activity (Rowley et al., 2012). In addition, LDX shows a much more moderate reinforcing effect in drug self-administration studies and a more time-dependent effect in drug-discrimination studies than other stimulant drugs (Heal et al., 2013a).
Importantly, LDX retained the efficacy observed with d-amphetamine in the delayed discounting model of impulsive behavior in keeping with its efficacy in the treatment of ADHD. However, there were some surprising differences between LDX and d-amphetamine at equivalent doses, including a blunting of both striatal dopamine efflux and consequent locomotor stimulant response and time to effect and potency differences in the drug discrimination and self-administration studies. These effects are relevant to the psychostimulant properties and abuse potential of LDX in humans and are probably a function of the rate of d-amphetamine entry into the brain. Rapid brain uptake of immediate-release d-amphetamine and subsequent dopamine release underpins the subjective “rush” experienced by drug abusers. Conversely, the slower generation of d-amphetamine from the pro-drug LDX has a blunted effect on dopamine function. However, it is important to note that because the active moiety of LDX is d-amphetamine, a known drug of abuse, it is classified as a Schedule II drug in the United States.
URL: https://www.sciencedirect.com/science/article/pii/S0028390814000781