Lisdexamfetamine

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Lisdexamfetamine
Systematic (IUPAC) name
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa607047
Pregnancy cat.C
Legal statusPharmacist only (AU) POM (UK) Schedule II (US)
RoutesOral
Pharmacokinetic data
Bioavailability28%
MetabolismGastro-intestinal (initial); Hepatic (extensively CYP2D6) after conversion to d-amphetamine
Half-life< 1 hour (prodrug molecule), 12-13 hours (d-amphetamine)
ExcretionRenal: ~2%
Identifiers
CAS number608137-32-2 YesY
ATC codeN06BA12
PubChemCID 11597698
DrugBankDB01255
ChemSpider9772458 YesY
UNIIH645GUL8KJ YesY
ChEMBLCHEMBL1201222 N
Synonyms(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide

(2S)-2,6-Bis(azanyl)-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Chemical data
FormulaC15H25N3O 
Mol. mass263.378 g/mol
 N (what is this?)  (verify)
 
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Lisdexamfetamine
Systematic (IUPAC) name
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa607047
Pregnancy cat.C
Legal statusPharmacist only (AU) POM (UK) Schedule II (US)
RoutesOral
Pharmacokinetic data
Bioavailability28%
MetabolismGastro-intestinal (initial); Hepatic (extensively CYP2D6) after conversion to d-amphetamine
Half-life< 1 hour (prodrug molecule), 12-13 hours (d-amphetamine)
ExcretionRenal: ~2%
Identifiers
CAS number608137-32-2 YesY
ATC codeN06BA12
PubChemCID 11597698
DrugBankDB01255
ChemSpider9772458 YesY
UNIIH645GUL8KJ YesY
ChEMBLCHEMBL1201222 N
Synonyms(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide

(2S)-2,6-Bis(azanyl)-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Chemical data
FormulaC15H25N3O 
Mol. mass263.378 g/mol
 N (what is this?)  (verify)
30mg Vyvanse capsules
40mg Vyvanse capsules
70mg Vyvanse capsules

Lisdexamfetamine dimesylate (L-lysine-D-amphetamine; sold as Vyvanse) is a psychostimulant prodrug of the phenethylamine and amphetamine chemical classes. Its molecular structure consists of dextroamphetamine coupled with the essential amino acid L-lysine.

Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule. It was developed for the intention of creating a longer-lasting and more difficult to abuse version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration, regardless of the route of ingestion.[1] The drug lisdexamfetamine dimesylate is the first prodrug of its kind. Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than d-amphetamine, and an abuse profile similar to diethylpropion at dosages that are FDA approved for treatment for ADHD, but still high abuse potential when this dosage is exceeded by over 100%.[2] There is no increased onset or effect as occurs with IV administration of dextroamphetamine compared to oral use of the same. Intravenously administered lisdexamfetamine produced likability effects similar to placebo, therefore affirming the drug's ability to reduce abuse potential.[3]

Lisdexamfetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children six to twelve years and in adults as an integral part of a total treatment program that may include other measures (i.e., psychological, educational, social). The safety and efficacy of lisdexamfetamine dimesylate in patients three to five years old have not been established.[4] Important side effects of therapeutic lisdexamfetamine include stunted growth in young people and occasionally a psychosis can occur at therapeutic doses during chronic therapy as a treatment emergent side effect.[5] When abused at high doses the risk of experiencing side effects and their severity increases.

As opposed to Adderall, which contains roughly 75% dextroamphetamine and 25% levoamphetamine, lisdexamfetamine is a single-enantiomer (dextro) amphetamine formula. This pure formulation may reduce side effects, but certain individuals exhibit a better clinical response to the mixed isomer preparation.[6]

Vyvanse is also being investigated for possible treatment of Major Depressive Disorder, cognitive impairment associated with Schizophrenia, Excessive Daytime Sleepiness, and Binge Eating Disorder.[7]

Contents

Dosage

Lisdexamfetamine is marketed under the brand name Vyvanse. Vyvanse comes in several dosages (see table below). These are usually labeled to be taken once daily.[8]

Vyvanse dosage strengths available[8]
StrengthAppearanceImprint (unique label)
20 milligramsCapsule with ivory colored body and capNRP104 or S489 20 mg
30 milligramsCapsule with white colored body and orange colored capNRP104 or S489 30 mg
40 milligramsCapsule with white colored body and teal colored capNRP104 or S489 40 mg
50 milligramsCapsule with white colored body and blue colored capNRP104 or S489 50 mg
60 milligramsCapsule with aqua blue colored body and capNRP104 or S489 60 mg
70 milligramsCapsule with blue colored body and orange colored capNRP104 or S489 70 mg

25 mg of Vyvanse is molecularly equivalent to 10 mg of Dexedrine (resulting in or including 7.37 mg versus 7.50 mg dextroamphetamine, respectively), although a 25 mg Vyvanse capsule is not commercially available.[9] However, the molecular equivalence ratio does not mean that the respective doses of Vyvanse and Dexedrine SR (Spansule) are bioequivalent because the two formulations have slightly different pharmacokinetic profiles. For example, while the area under the curve for the aforementioned pharmaceuticals is equivalent, the peak exposure (Cmax) to the active compound dextroamphetamine is about 50% higher for Vyvanse than for Dexedrine SR.[9] The conversion rate of lisdexamfetamine to dextroamphetamine base is 0.2948,[10] meaning that each milligram of lisdexamfetamine is equivalent to 0.2948 mg of dextroamphetamine base.

Mechanism of action

Because lisdexamphetamine is active in the human brain as amphetamine, its mechanism of action is identical to the mechanism of action of amphetamine.

Although the precise mechanism of action by which amphetamines improve the symptoms of ADHD remains unknown, they are thought to block the reuptake of norepinephrine (noradrenaline) and dopamine into the presynaptic neuron and increase their availability into the extraneuronal space.[11]

Lisdexamfetamine (LDX) is a therapeutically inactive molecule. After oral ingestion, LDX is broken down by enzymes to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for the drug’s activity. The conversion of LDX to d-amphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times. LDX was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse-related liking. The attachment of the amino acid lysine slows down the relative amount of d-amphetamine available to the blood stream. Because no free d-amphetamine is present in LDX capsules, d-amphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to obtain d-amphetamine from LDX.[12]

History

Vyvanse was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. Vyvanse is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit hyperactivity disorder.

On April 23, 2008, Vyvanse received FDA approval for the adult population.[13] In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, 30, 50 or 70mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo.[14]

On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[15]

On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[16]

Side effects

Misuse potential

Lisdexamfetamine has less potential for misuse than its active metabolite (dextroamphetamine) due to being initially inactive upon consumption via all methods and the drug level of the active metabolite dextroamphetamine reaching a plateau within a therapeutic dosage range (both results of being a pro-drug).

Common side effects

Common side effects (side effects that have average rates of presentation; usually presenting in >5% of patients) of lisdexamfetamine use may include:[8][17]

Severe side effects include

Other side effects can be caused by lisdexamfetamine; these potentially serious reactions may include:[8][17]

See also

References

  1. ^ Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in Children and Adults
  2. ^ Jasinski, DR and S Krishnan. "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse." Journal of Psychopharmacology 23, no. 4 (2009): 419-427. doi:10.1177/0269881109103113.
  3. ^ Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers.
  4. ^ "Lisdexamfetamine dimesylate (generic)." Brown University Psychopharmacology Update 19.7 (2008): 1-2. Academic Search Premier. EBSCO. Web. 12 Sept. 2010.
  5. ^ a b Berman, SM.; Kuczenski, R.; McCracken, JT.; London, ED. (Feb 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review.". Mol Psychiatry 14 (2): 123–42. doi:10.1038/mp.2008.90. PMID 18698321.
  6. ^ "Vyvanse Vs. Adderall
  7. ^ http://www.shire.com/shireplc/en/rd/pipeline
  8. ^ a b c d Vyvanse (Lisdexamfetamine Dimesylate) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList
  9. ^ a b FDA Approval of Vyvanse – Pharmacological Reviews
  10. ^ Moore, Elaine.The Amphetamine Debate: The Use of Adderall, Ritalin and Related Drugs for Behavior Modification, Neuroenhancement and Anti-Aging Purposes. McFarland, 2010, p. 91.
  11. ^ Katherine A. Lyseng-Williamson. "Lisdexamfetamine dimesylate: a guide to its use in attention-deficit hyperactivity disorder." Drugs & Therapy Perspectives 26, no. 10 (2010): 1-5.
  12. ^ Jasinski, DR and S Krishnan. "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse." Journal of Psychopharmacology 23, no. 4 (2009): 419-427. doi:10.1177/0269881109103113.
  13. ^ FDA Adult Approval of Vyvanse - FDA Label and Approval History
  14. ^ Weber J, Siddiqui, MA. [1].CNSDrugs 2009; 23(5): 419-425. doi:10.2165/00023210-200923050-00005.
  15. ^ Health Canada Notice of Compliance - Vyvanse. February 19, 2009, retrieved on March 9, 2009.
  16. ^ [2]. February 8, 2012, retrieved on February 9, 2012.
  17. ^ a b Lisdexamfetamine Capsules Facts and Comparisons at Drugs.com