Educational guide
Lisdexamfetamine - an overview
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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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-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
Abstract
Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007–2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.
URL: https://www.sciencedirect.com/science/article/pii/S0928098716301324
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
Lisdexamfetamine Dimesylate.
Lisdexamfetamine dimesylate is a prodrug that is metabolized to dextroamphetamine and is available as Vyvanse. It was designed to reduce abuse potential because dextroamphetamine is released only after the removal of l-lysine. This prodrug preparation is approved for children who are older than 5 years of age. The peak concentration of lisdexamfetamine occurs in 1 hour, while the maximum dextroamphetamine concentration does not occur until 3.5 hours after ingestion. Lisdexamfetamine dimesylate is available in 30-, 50-, and 70-mg capsules and is administered in the morning. The capsule may be swallowed whole or may be dissolved in a glass of water.
The initial recommended dose of lisdexamfetamine dimesylate is 30 mg/day, with dose adjustments of 20 mg/wk. The maximum recommended dose of lisdexamfetamine is 70 mg.
URL: https://www.sciencedirect.com/science/article/pii/B978141603291550055X
4.5 Not the substance itself, but its active metabolite that is of concern - lisdexamfetamine
One of the determinative factors for schedule control actions is whether the NME is a precursor or prodrug of any drug already scheduled under the CSA (Factor 8). Factor 8 has little to do with the three abuse liability studies described in the FDA guidance document. Lisdexamfetamine does not readily cross the BBB and has no major peripheral effects on its own (Coghill et al., 2014). As a precursor or prodrug, lisdexamfetamine is a biologically inactive compound that can be metabolized in the body to produce amphetamine, a Schedule II controlled substance. Various long-acting psychomotor stimulants like amphetamine and methylphenidate have been developed, with the aim of relieving symptoms associated with attention deficit/hyperactivity disorder (ADHD; Hodgkins et al., 2012). Lisdexamfetamine dimesylate (LDX) was the first long-acting prodrug stimulant for the treatment of ADHD. After ingestion and absorption, LDX is enzymatically hydrolyzed to release the therapeutically active moiety dextro-amphetamine (d-AMP; Penick, 2010). Pharmacokinetic studies in humans have shown that exposure to d-AMP following oral administration of LDX is monophasic, sustained, and dose proportional, with low intra- and inter-patient variability. The pharmacodynamics properties of LDX following a single therapeutic dose of LDX shows a maximum plasma concentration of d-AMP of 3.5 h after a single dose of LDX in children with ADHD, with an elimination half-life ranging from 8.61 to 8.90 h. The ‘high’ associated street-wise stimulant abuse like methamphetamine injections, has been linked to its rapid rise in stimulant concentration and the resultant increase in monoamine receptor occupancy (Volkow and Swanson, 2003). Accordingly, the absence of an early sharp rise and spike in systemic d-AMP concentrations following LDX administration was believed to lead to a lower abuse potential compared with immediate-release d-AMP formulations (Jasinski and Krishman, 2009). These pharmacological data submitted by the FDA in their independent 8 factor analysis are legally binding on the DEA but are irrelevant to the scheduling actions required under the 8-factor analysis. Since lisdexamfetamine is a prodrug of amphetamine the drug must be placed into Schedule II of the CSA, as a matter of law regardless of the rate of entry into the CNS. This non-CNS acting drug becomes active as a biological product of gut (peripheral) metabolic processes. These ‘second-stage’ metabolic processes may apply to future biologics coming up for schedule review.
URL: https://www.sciencedirect.com/science/article/pii/S0273230018303015
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
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