Lisdexamfetamine

Identification

Summary

Lisdexamfetamine is a central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) and moderate to severe eating disorders.

Brand Names
Vyvanse
Generic Name
Lisdexamfetamine
DrugBank Accession Number
DB01255
Background

Lisdexamfetamine is a prodrug of dextroamphetamine, a central nervous system stimulant known as d-amphetamine,3 covalently attached to the naturally occurring amino acid L-lysine.1 Lisdexamfetamine is the first chemically formulated prodrug stimulant 3 and was first approved by the FDA in April 2008.1 It was also approved by Health Canada in February 2009.7 Lisdexamfetamine works to treat attention deficit hyperactivity disorder and binge eating disorder 1 by blocking dopamine and norepinephrine reuptake and increasing their levels in the extraneuronal space.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 263.3785
Monoisotopic: 263.199762437
Chemical Formula
C15H25N3O
Synonyms
  • Lisdexamfetamine

Pharmacology

Indication

Lisdexamfetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients six years and older. It is also indicated to treat moderate to severe binge eating disorder (BED) in adults.6,7 It is approved for use in the US and Canada.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofAdhd••••••••••••••••••••••• •••••• •••••••••
Management ofModerate binge eating disorder (bed)•••••••••••••••••
Management ofSevere binge eating disorder (bed)•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Once administered, lisdexamfetamine is converted to its active metabolite, dextroamphetamine, which is taken up by the brain. Dextroamphetamine blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.6

Mechanism of action

Lisdexamfetamine is a prodrug of dextroamphetamine, which is a noncatecholamine sympathomimetic amine with CNS stimulant activity. Dextroamphetamine is a known inhibitor of the dopamine transporter (DAT), noradrenaline transporter (NET) and vesicular monoamine transporter 2 (VMAT2), with a weaker affinity for the serotonin transporter (SERT). It is also a weak monoamine oxidase (MAO) inhibitor.4 Dextroamphetamine ultimately blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases catecholamine availability in the extracellular space.6

The exact mode of therapeutic action of lisdexamfetamine in ADHD and BED has not been fully elucidated; however, the clinical effects of lisdexamfetamine are believed to be linked to the pharmacological actions of dextroamphetamine.4,6

TargetActionsOrganism
UTrace amine-associated receptor 1
agonist
Humans
Absorption

After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract.3,7 Following single-dose oral administration of lisdexamfetamine in pediatric patients with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately one hour and 3.5 hours post-dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients as the adults. Food prolongs Tmax by approximately one hour and may decrease the exposure (Cmax and AUC) of dextroamphetamine.6

Volume of distribution

Dextroamphetamine, the active metabolite of lisdexamfetamine, easily crosses the blood-brain barrier.4

Protein binding

Not Available

Metabolism

Lisdexamfetamine dimesylate is hydrolyzed by red blood cells to dextroamphetamine and l-lysine primarily in the blood. Substantial hydrolysis occurs even at low hematocrit levels.3,4,6 Dextroamphetamine can further be metabolized to form other metabolites, such as hippuric acid.5

Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.2,6

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Route of elimination

Following oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate in six healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine, and only 0.3% recovered in the feces over 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine.6

Half-life

Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in volunteers ages six years and older. The plasma elimination half-life of dextroamphetamine was approximately 8.6 to 9.5 hours in pediatric patients six to 12 years and 10 to 11.3 hours in healthy adults.6

Clearance

Not Available

Adverse Effects
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Toxicity

The LD50 value for lisdexamfetamine dihydrochloride in rats was >1000 mg/kg.7

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including lisdexamfetamine. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Convulsions and coma usually precede fatal poisoning. Lisdexamfetamine and d-amphetamine are not dialyzable.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbirateroneThe serum concentration of dextroamphetamine, an active metabolite of Lisdexamfetamine, can be increased when used in combination with Abiraterone.
AcebutololThe serum concentration of dextroamphetamine, an active metabolite of Lisdexamfetamine, can be increased when used in combination with Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Lisdexamfetamine is combined with Aceclofenac.
AcemetacinThe risk or severity of hypertension can be increased when Lisdexamfetamine is combined with Acemetacin.
AcetazolamideAcetazolamide may decrease the excretion rate of Lisdexamfetamine which could result in a higher serum level.
Food Interactions
  • Avoid antacids. Urinary excretion of lisdexamfetamine is elevated when the urine is more acidic. Antacids like sodium bicarbonate alkalinize the urine; therefore, they may reduce lisdexamfetamine elimination.
  • Limit foods and supplements high in vitamin C. Urinary excretion of lisdexamfetamine is elevated when the urine is more acidic. Vitamin C acidifies the urine and, therefore, may increase lisdexamfetamine elimination.
  • Take with or without food. Food prolongs Tmax by approximately one hour, but does not significantly affect drug exposure.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Lisdexamfetamine dimesylateSJT761GEGS608137-33-3CETWSOHVEGTIBR-FORAGAHYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VyvanseTablet, chewable40 mg/1OralTakeda Pharmaceuticals America, Inc.2017-01-28Not applicableUS flag
VyvanseCapsule70 mgOralTakeda2017-01-05Not applicableCanada flag
VyvanseCapsule70 mg/1OralPhysicians Total Care, Inc.2010-03-04Not applicableUS flag
VyvanseTablet, chewable10 mg/1OralTakeda Pharmaceuticals America, Inc.2017-01-28Not applicableUS flag
VyvanseCapsule70 mg/1OralTakeda Pharmaceuticals America, Inc.2007-02-23Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Lisdexamfetamine DimesylateCapsule10 mg/1OralLannett Company, Inc.2023-08-25Not applicableUS flag
Lisdexamfetamine dimesylateTablet, chewable60 mg/1OralNovadoz Pharmaceuticals Llc2024-02-02Not applicableUS flag
Lisdexamfetamine DimesylateCapsule40 mg/1OralHikma Pharmaceuticals USA Inc.2023-08-25Not applicableUS flag
Lisdexamfetamine DimesylateTablet, chewable40 mg/1OralAscent Pharmaceuticals, Inc2023-08-25Not applicableUS flag
Lisdexamfetamine DimesylateCapsule10 mg/1OralSpecGx LLC2023-08-25Not applicableUS flag

Categories

ATC Codes
N06BA12 — Lisdexamfetamine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Amphetamines and derivatives / Phenylpropanes / N-acyl amines / Secondary carboxylic acid amides / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alpha-amino acid amide / Amine / Amphetamine or derivatives / Aromatic homomonocyclic compound / Benzenoid / Carbonyl group / Carboxamide group / Fatty acyl / Fatty amide / Hydrocarbon derivative
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
H645GUL8KJ
CAS number
608137-32-2
InChI Key
VOBHXZCDAVEXEY-JSGCOSHPSA-N
InChI
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
IUPAC Name
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
SMILES
C[C@@H](CC1=CC=CC=C1)NC(=O)[C@@H](N)CCCCN

References

Synthesis Reference

Michael J. Bauer, Gary Richard Callen, Judi Christine Humphrey, Todd Jeffrey Johnson, Matthew Wendell Schiesher, "Methods and Compositions for Preparing Lisdexamfetamine and Salts Thereof." U.S. Patent US20120157706, issued June 21, 2012.

US20120157706
General References
  1. Madaan V: Lisdexamfetamine dimesylate for childhood ADHD. Drugs Today (Barc). 2008 May;44(5):319-24. doi: 10.1358/dot.2008.44.5.1215724. [Article]
  2. Krishnan S, Moncrief S: An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes. Drug Metab Dispos. 2007 Jan;35(1):180-4. Epub 2006 Oct 11. [Article]
  3. Goodman DW: Lisdexamfetamine dimesylate (vyvanse), a prodrug stimulant for attention-deficit/hyperactivity disorder. P T. 2010 May;35(5):273-87. [Article]
  4. Hutson PH, Pennick M, Secker R: Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug. Neuropharmacology. 2014 Dec;87:41-50. doi: 10.1016/j.neuropharm.2014.02.014. Epub 2014 Mar 1. [Article]
  5. Krishnan SM, Pennick M, Stark JG: Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers. Clin Drug Investig. 2008;28(12):745-55. doi: 10.2165/0044011-200828120-00002. [Article]
  6. FDA Approved Drug Products: VYVANSE (lisdexamfetamine dimesylate) capsules and chewable tablets, for oral use, CII (January 2022) [Link]
  7. Health Canada Approved Drug Products: VYVANSE (lisdexamfetamine dimesylate) Oral Capsules [Link]
Human Metabolome Database
HMDB0015385
PubChem Compound
11597698
PubChem Substance
46505358
ChemSpider
9772458
RxNav
700810
ChEBI
135925
ChEMBL
CHEMBL1201222
ZINC
ZINC000011680943
Therapeutic Targets Database
DAP000571
PharmGKB
PA164748975
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lisdexamfetamine

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • New River Pharmaceuticals Inc.
  • Patheon Inc.
  • Physicians Total Care Inc.
  • Quality Care
  • Shire Inc.
Dosage Forms
FormRouteStrength
Capsule, coatedOral70 mg
Capsule, coatedOral30 mg
Capsule, coatedOral50 mg
CapsuleOral10 mg/1
CapsuleOral10 mg
CapsuleOral20 mg/1
CapsuleOral20 mg
CapsuleOral30 mg/1
CapsuleOral30 mg
CapsuleOral30.000 mg
CapsuleOral40 mg
CapsuleOral40 mg/1
CapsuleOral50 mg
CapsuleOral50 mg/1
CapsuleOral60 mg
CapsuleOral60 mg/1
CapsuleOral70 mg
CapsuleOral70 mg/1
Tablet, chewableOral10 mg/1
Tablet, chewableOral10 mg
Tablet, chewableOral20 mg/1
Tablet, chewableOral20 mg
Tablet, chewableOral30 mg/1
Tablet, chewableOral30 mg
Tablet, chewableOral40 mg
Tablet, chewableOral40 mg/1
Tablet, chewableOral50 mg
Tablet, chewableOral50 mg/1
Tablet, chewableOral60 mg/1
Tablet, chewableOral60 mg
CapsuleOral20.0 mg
CapsuleOral30.0 mg
CapsuleOral40.0 mg
CapsuleOral50.0 mg
CapsuleOral60.0 mg
CapsuleOral70.0 mg
Capsule, coatedOral20 mg
Capsule, coatedOral40 mg
Capsule, coatedOral60 mg
Prices
Unit descriptionCostUnit
Vyvanse 30 mg capsule6.24USD capsule
Vyvanse 50 mg capsule6.02USD capsule
Vyvanse 70 mg capsule5.85USD capsule
Vyvanse 40 mg capsule5.8USD capsule
Vyvanse 20 mg capsule5.26USD capsule
Vyvanse 60 mg capsule5.02USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7659253Yes2010-02-092023-08-24US flag
US7718619Yes2010-05-182023-08-24US flag
US7659254Yes2010-02-092023-08-24US flag
US7671030Yes2010-03-022023-08-24US flag
US7662788Yes2010-02-162023-08-24US flag
US7687467Yes2010-03-302023-08-24US flag
US7678770Yes2010-03-162023-08-24US flag
US7671031Yes2010-03-022023-08-24US flag
US7713936Yes2010-05-112023-08-24US flag
US7674774Yes2010-03-092023-08-24US flag
US7678771Yes2010-03-162023-08-24US flag
US7655630Yes2010-02-022023-08-24US flag
US7687466Yes2010-03-302023-08-24US flag
US7223735Yes2007-05-292023-08-24US flag
US7700561Yes2010-04-202023-08-24US flag
US7662787Yes2010-02-162023-08-24US flag
US7723305Yes2010-05-252023-08-24US flag
US7105486Yes2006-09-122023-08-24US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)191-193https://www.trc-canada.com/prod-img/MSDS/L468885MSDS.pdf
water solubility792 mg/mLhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021977s048,208510s005lbl.pdf
logP-1.76https://www.tga.gov.au/sites/.../auspar-lisdexamfetamine-dimesilate-131023-pi.docx
pKa10.5https://www.tga.gov.au/sites/.../auspar-lisdexamfetamine-dimesilate-131023-pi.docx
Predicted Properties
PropertyValueSource
Water Solubility0.0877 mg/mLALOGPS
logP1.01ALOGPS
logP1.14Chemaxon
logS-3.5ALOGPS
pKa (Strongest Acidic)15.89Chemaxon
pKa (Strongest Basic)10.21Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area81.14 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity78.31 m3·mol-1Chemaxon
Polarizability31.28 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9858
Blood Brain Barrier+0.9444
Caco-2 permeable+0.664
P-glycoprotein substrateSubstrate0.6919
P-glycoprotein inhibitor INon-inhibitor0.9264
P-glycoprotein inhibitor IINon-inhibitor0.9802
Renal organic cation transporterNon-inhibitor0.8398
CYP450 2C9 substrateNon-substrate0.8303
CYP450 2D6 substrateNon-substrate0.621
CYP450 3A4 substrateNon-substrate0.7228
CYP450 1A2 substrateNon-inhibitor0.7025
CYP450 2C9 inhibitorNon-inhibitor0.9337
CYP450 2D6 inhibitorNon-inhibitor0.858
CYP450 2C19 inhibitorNon-inhibitor0.7568
CYP450 3A4 inhibitorNon-inhibitor0.5499
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8494
Ames testNon AMES toxic0.7156
CarcinogenicityNon-carcinogens0.854
BiodegradationNot ready biodegradable0.8575
Rat acute toxicity2.0058 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9688
hERG inhibition (predictor II)Non-inhibitor0.9004
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0udi-7910000000-cf67fb00e86045c2e167
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-0290000000-24fbe6074a7ff645887c
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03gl-2890000000-f4bffe135c3f75f90f40
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-6940000000-704d606c65e51f253bee
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-005d-9810000000-027326415aaf04017fdc
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-9200000000-0887b5e4f9bbe3580fd8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9300000000-b66be0a84f8848fbc99a
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-171.9992286
predicted
DarkChem Lite v0.1.0
[M-H]-170.5049286
predicted
DarkChem Lite v0.1.0
[M-H]-164.69353
predicted
DeepCCS 1.0 (2019)
[M+H]+172.1414286
predicted
DarkChem Lite v0.1.0
[M+H]+170.7083286
predicted
DarkChem Lite v0.1.0
[M+H]+167.08965
predicted
DeepCCS 1.0 (2019)
[M+Na]+172.3272286
predicted
DarkChem Lite v0.1.0
[M+Na]+170.6377286
predicted
DarkChem Lite v0.1.0
[M+Na]+173.47252
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Trace-amine receptor activity
Specific Function
Receptor for trace amines, including beta-phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amin...
Gene Name
TAAR1
Uniprot ID
Q96RJ0
Uniprot Name
Trace amine-associated receptor 1
Molecular Weight
39091.34 Da
References
  1. Miller GM: The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem. 2011 Jan;116(2):164-76. doi: 10.1111/j.1471-4159.2010.07109.x. [Article]
  2. Liu JF, Li JX: TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg. Front Pharmacol. 2018 Mar 27;9:279. doi: 10.3389/fphar.2018.00279. eCollection 2018. [Article]
  3. Pei Y, Asif-Malik A, Canales JJ: Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Front Neurosci. 2016 Apr 5;10:148. doi: 10.3389/fnins.2016.00148. eCollection 2016. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
These data are based on in vitro studies.
General Function
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Pennick M: Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010 Jun 24;6:317-27. [Article]
  2. Elvanse EPAR [File]

Drug created at May 15, 2007 01:24 / Updated at September 28, 2023 05:40