Lisdexamfetamine

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Lisdexamfetamine
Lisdexamfetamine structure.svg
Lisdexamfetamine ball-and-stick model.png
Names
Trade namesTyvense, Elvanse, Vyvanse, others
Other names(2S)-2,6-Diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
N-[(2S)-1-Phenyl-2-propanyl]-L-lysinamide
  • (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide
Clinical data
Drug classCentral nervous system (CNS) stimulant[1][2]
Main usesADHD, binge eating disorder[1]
Side effectsLoss of appetite, anxiety, diarrhea, trouble sleeping, irritability, nausea[1]
Dependence riskHigh[1][5]
Addiction riskModerate
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
use
By mouth (capsules)
Onset of action2 h[3][4]
Duration of action10–12 h[5][3][4]
Defined daily dose30 mg[6]
External links
AHFS/Drugs.comMonograph
MedlinePlusa607047
Legal
License data
Legal status
Pharmacokinetics
Bioavailability96.4%[7]
MetabolismHydrolysis by enzymes in red blood cells initially.
Subsequent metabolism follows Amphetamine#Pharmacokinetics.
Elimination half-life≤1 h (prodrug molecule)
9–11 h (dextroamphetamine)
ExcretionRenal: ~2%
Chemical and physical data
FormulaC15H25N3O
Molar mass263.385 g·mol−1
3D model (JSmol)
  • O=C(N[C@H](Cc1ccccc1)C)[C@@H](N)CCCCN
  • InChI=1S/C15H25N3O/c1-12(11-13-7-3-2-4-8-13)18-15(19)14(17)9-5-6-10-16/h2-4,7-8,12,14H,5-6,9-11,16-17H2,1H3,(H,18,19)/t12-,14-/m0/s1 checkY
  • Key:VOBHXZCDAVEXEY-JSGCOSHPSA-N checkY

Lisdexamfetamine, sold under the brand name Vyvanse among others, is a medication that is used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as for moderate to severe binge eating disorder in adults.[1] Lisdexamfetamine is taken by mouth.[1][8] In the United Kingdom it is usually less preferred than methylphenidate.[9] Its effects generally begin within 2 hours and last for up to 12 hours.[1]

Common side effects include loss of appetite, anxiety, diarrhea, trouble sleeping, irritability, and nausea.[1] Rare but serious side effects include mania, sudden cardiac death in those with underlying heart problems, and psychosis.[1] It has a high potential for abuse per the DEA.[1][8] Serotonin syndrome may occur if used with certain other medications.[1] Its use during pregnancy may result in harm to the baby and use during breastfeeding is not recommended by the manufacturer.[9][1][8] Lisdexamfetamine is a central nervous system (CNS) stimulant that works after being converted by the body into dextroamphetamine.[1][2] Chemically, lisdexamfetamine is composed of the amino acid L-lysine, attached to dextroamphetamine.[10]

Lisdexamfetamine was approved for medical use in the United States in 2007.[1] A month's supply in the United Kingdom costs the British National Health Service about £58 as of 2019.[9] In the United States, the wholesale cost of this amount is about US$264.[11] In 2017, it was the 91st most commonly prescribed medication in the United States, with more than eight million prescriptions.[12][13] It is a Schedule II controlled substance in the United Kingdom and a Schedule II controlled substance in the United States.[9][14]

Uses

Medical

30mg Vyvanse capsules

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder;[15] it has similar off-label uses as those of other pharmaceutical amphetamines.[5] Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD.[15]

Cognitive performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[16][17] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[18][16] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[19] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[18][20] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[18][21][22] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.[18][22][23] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[24][25][26] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[18][22]

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[27][28] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[29][30] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.[27][31][32] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[31][32][33] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[32][34][35] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[27][31] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[36][31]

Dosage

The defined daily dose is 30 mg by mouth.[6]

Contraindications

Pharmaceutical lisdexamfetamine dimesylate is contraindicated in patients with hypersensitivity to amphetamine products or any of the formulation's inactive ingredients.[15] It is also contraindicated in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days.[15][37] Amphetamine products are contraindicated by the United States Food and Drug Administration (USFDA) in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[38] The USFDA advises anyone with bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking amphetamine.[38] Amphetamine is classified in US pregnancy category C.[38] This means that detriments to the fetus have been observed in animal studies and adequate human studies have not been conducted; amphetamine may still be prescribed to pregnant women if the potential benefits outweigh the risks.[39] Amphetamine has also been shown to pass into breast milk, so the USFDA advises mothers to avoid breastfeeding when using it.[38] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[38] Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.[40]

Side effects

Products containing lisdexamfetamine have a comparable drug safety profile to those containing amphetamine.[10]

Interactions

  • Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of dextroamphetamine, thus decreasing the half-life of dextroamphetamine in the body.[15][41]
  • Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of dextroamphetamine, thus increasing the half-life of dextroamphetamine in the body.[15][41]
  • Monoamine Oxidase Inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as lisdexamfetamine can cause a hypertensive crisis.[15]

Mechanism of action

Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[42] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[42][43] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[43][44] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylates DAT.[42][45][46] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[42] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[42] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[47][48]

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug's activity.[49] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.[15] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[15][50]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;[42][43] this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.[42][43]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.[50] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[49][51] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[50]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[36] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[52] Amphetamine is a weak base with a pKa of 9.9;[53] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[53][36] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[53] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[54] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[55]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[53] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[53] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[55] highly alkaline urine will increase the half-lives up to 34 hours.[55] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[53] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[53] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[53] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[53] Following oral administration, amphetamine appears in urine within 3 hours.[55] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[55] 

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[15] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[15] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[15]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 1] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[53][56] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[57] 4-hydroxynorephedrine,[58] and norephedrine.[59] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[53][60] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[56] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[53] The remaining 10–20% is excreted as the active metabolites.[53] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[66]

Chemistry

Lisdexamfetamine is a substituted amphetamine with an amide linkage formed by the condensation of dextroamphetamine with the carboxylate group of the essential amino acid L-lysine.[10] The reaction occurs with retention of stereochemistry, so the product lisdexamfetamine exists as a single stereoisomer. There are many possible names for lisdexamfetamine based on IUPAC nomenclature, but it is usually named as N-[(2S)-1-phenyl-2-propanyl]-L-lysinamide or (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide.[70] The condensation reaction occurs with loss of water:

(S)-PhCH
2
CH(CH
3
)NH
2
  +   (S)-HOOCCH(NH
2
)CH
2
CH
2
CH
2
CH
2
NH
2
  →   (S,S)-PhCH
2
CH(CH
3
)NHC(O)CH(NH
2
)CH
2
CH
2
CH
2
CH
2
NH
2
  +   H
2
O

Amine functional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. This increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product.[71] In the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble (792 mg mL−1) powder with a white to off-white color.[15]

PhCH
2
CH(CH
3
)NHC(O)CH(NH
2
)CH
2
CH
2
CH
2
CH
2
NH
2
  +   2 CH
3
SO
3
H
  →   [PhCH
2
CH(CH
3
)NHC(O)CH(NH+
3
)CH
2
CH
2
CH
2
CH
2
NH+
3
]
[CH
3
SO
3
]
2

Comparison to other formulations

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 2]
amphetamine base
[note 3]
amphetamine base
in equal doses
doses with
equal base
content
[note 4]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[73][74] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[75] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
11.0 mg
11.0 mg
30.0 mg
Adderall
62.57%
47.49%
15.08%
14.2 mg
4.5 mg
35.2 mg
25% dextroamphetamine sulfate[73][74] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[75] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[76] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[77] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[15] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[78] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

History, society, and culture

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Takeda Pharmaceuticals through its acquisition of Shire Pharmaceuticals, shortly before it began being marketed. It was developed with the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells delays its onset of action, regardless of the route of administration.[79]

On 23 April 2008, the FDA approved lisdexamfetamine for treatment of ADHD in adults.[80] On 19 February 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[81]

In January 2015, lisdexamfetamine was approved by the U.S. Food and Drug Administration for treatment of binge eating disorder in adults.[82]

Production quotas for 2016 in the United States were 29,750 kilograms.[83]

Names

Lisdexamfetamine is a contraction of L-lysine-dextroamphetamine.

As of July 2014 lisdexamfetamine was sold under the following brands: Elvanse, Samexid, Tyvense, Venvanse, and Vyvanse.[84]

Research

Depression

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone.[85] Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment resistant depression. In those studies, patients showed significant improvement in energy, mood, and psychomotor activity.[86] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[87]

Society and culture

Cost

A month's supply in the United Kingdom costs the British National Health Service about £58 as of 2019.[9] In the United States, the wholesale cost of this amount is about US$264.[11] In 2017, it was the 91st most commonly prescribed medication in the United States, with more than eight million prescriptions.[12][13]

Notes

  1. 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[61][65] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[65][67] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[68][69]
  2. For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[72] and were within 0.01g/mol of published pharmaceutical values.
  3. Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  4. dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
Image legend

Reference notes

References

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    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
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    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
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    Physiologic and performance effects
     • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     • Improved reaction time
     • Increased muscle strength and delayed muscle fatigue
     • Increased acceleration
     • Increased alertness and attention to task
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