Armodafinil

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Armodafinil
Armodafinil structure.svg
Armodafinil ball-and-stick xtal 2013.png
Clinical data
Trade names Nuvigil, others
AHFS/Drugs.com Monograph
MedlinePlus a602016
Pregnancy
category
  • C
Dependence
liability		 Low
Routes of
administration		 Oral (tablets)
ATC code N06BA13 (WHO)
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver, including CYP3A4 and other pathways
Biological half-life 12–15 hours
Excretion Urine (as metabolites)
Identifiers
CAS Number 112111-43-0 N
PubChem (CID) 9690109
ChemSpider 7962943 YesY
UNII V63XWA605I YesY
KEGG D03215 YesY
ChEBI CHEBI:77590 N
ChEMBL CHEMBL1201192 N
ECHA InfoCard 100.207.833
Chemical and physical data
Formula C15H15NO2S
Molar mass 273.35 g·mol−1
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Armodafinil (trade name Nuvigil) is the enantiopure of the wakefulness-promoting agent,[1] or eugeroic, modafinil (Provigil). It consists of just the (R)-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc.[2] and was approved by the U.S. Food and Drug Administration (FDA) in June 2007.[3][4]

Although they have similar half-lives, armodafinil reaches its peak concentration in the blood later after administration than modafinil does, which may make it more effective at improving wakefulness in patients with excessive daytime sleepiness.[5]

Medical uses[edit]

Armodafinil is currently FDA-approved to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder.[2] It is commonly used off-label to treat attention deficit hyperactivity disorder, chronic fatigue syndrome, and major depressive disorder. It has been shown to improve vigilance in air traffic controllers.[6]

Sleep disorders[edit]

Armodafinil is approved by the U.S. FDA for the treatment of narcolepsy and shift work sleep disorder, and as an adjuvant therapy for obstructive sleep apnea.[7] For narcolepsy and obstructive sleep apnea, armodafinil is taken as a once daily 150 mg or 250 mg dose in the morning. For shift work sleep disorder, 150 mg of armodafinil are taken one hour prior to starting work. Slow dose titration is needed to mitigate some side effects.[7]

Investigational[edit]

Schizophrenia[edit]

In June, 2010, it was revealed that a phase II study of armodafinil as an adjunctive therapy in adults with schizophrenia had failed to meet the primary endpoints, and the clinical program was subsequently terminated.[8] However, a study published later that year showed that schizophrenic patients treated with armodafinil showed fewer of the negative symptoms of schizophrenia.[9]

Jet lag[edit]

On March 30, 2010, the FDA declined to approve use of Nuvigil to treat jet lag.[10][11]

Adverse effects[edit]

In placebo-controlled studies, the most commonly observed side effects were headache, xerostomia (dry mouth), nausea, dizziness, and insomnia.

Possible side effects include depression, anxiety, hallucinations, euphoria, extreme increase in activity and talking, anorexia, tremor, thirst, rash, suicidal thoughts, and aggression.

Symptoms of an overdose on modafinil include trouble sleeping, restlessness, confusion, disorientation, feeling excited, mania, hallucinations, nausea, diarrhea, severely increased or decreased heart beat, chest pain, and increased blood pressure.[2][12] [13]

Pharmacology[edit]

Pharmacodynamics[edit]

The mechanism of action of armodafinil is unknown. Armodafinil (R-(−)-modafinil) has pharmacological properties almost identical to those of modafinil (a mixture of R-(−)- and (S)-(+)-modafinil). The (R)- and (S)-enantiomers have similar pharmacological action in animals. Armodafinil has wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil is an indirect dopamine receptor agonist; it binds in vitro to the dopamine transporter (DAT) and inhibits dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels. In genetically engineered mice lacking the dopamine transporter, modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.

In addition to its wake-promoting effects and ability to increase locomotor activity in animals, according to Nuvigil prescribing information from manufacturer Cephalon, armodafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other central nervous system (CNS) stimulants in humans.[2] Armodafinil, like racemic modafinil, may also possess reinforcing properties, as evidenced by its self-administration in monkeys previously trained to administer cocaine; armodafinil was also partially discriminated as stimulant-like. A Cephalon-founded study in which patients were administered modafinil, methylphenidate, and a placebo found that modafinil produces "psychoactive and euphoric effects and feelings consistent with [methylphenidate]."[2]

Pharmacokinetics[edit]

Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50–400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the (R)-(−)-enantiomer following a single dose of 50 mg Nuvigil or 100 mg Provigil (modafinil being a 1:1 mixture of (R)-(−)- and (S)-(−)- enantiomers) are nearly superimposable. However, the Cmax of armodafinil at steady state was 37% higher following administration of 200 mg Nuvigil than the corresponding value of modafinil following administration of 200 mg Provigil due to the more rapid clearance of the (S)-(+)-enantiomer.

Absorption[edit]

Armodafinil is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration may be delayed 2–4 hours in the fed state. Since the delay in Tmax is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.

Marketing[edit]

Brand names[edit]

Armodafinil is sold under a wide variety of brand names worldwide:

  • Acronite (by Consern Pharma) — India
  • Armod — India (discontinued)
  • Artvigil — India
  • Neoresotyl — Chile
  • Nuvigil — USA
  • R-Modawake — India
  • Waklert — India

See also[edit]

References[edit]

  1. ^ Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV (January 1998). "Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil". Neurosci. Lett. 241 (2-3): 95–8. doi:10.1016/s0304-3940(97)00962-2. PMID 9507929. 
  2. ^ a b c d e http://www.nuvigil.com/PDF/Full_Prescribing_Information.pdf
  3. ^ "CDER Drug and Biologic Approvals for Calendar Year 2007" (PDF). Retrieved 2008-01-21. 
  4. ^ "Search results from the "OB_Rx" table for query on "021875."", Orange Book, U.S. Food and Drug Administration, March 2012, retrieved April 30, 2012 
  5. ^ Darwish, M.; Kirby, M.; Hellriegel, E. T.; Robertson Jr, P. (2009). "Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives". Clinical Drug Investigation. 29 (9): 613–623. doi:10.2165/11315280-000000000-00000. PMID 19663523. 
  6. ^ Phillips, J. B.; Simmons, R. G.; Arnold, R. D. (2011). "A single dose of armodafinil significantly promotes vigilance 11 hours post-dose". Military medicine. 176 (7): 833–839. PMID 22128728. 
  7. ^ a b RXList-nuvigil
  8. ^ "Cephalon Provides Clinical Update on Phase II Study of NUVIGIL as an Adjunctive Therapy in Adults with Schizophrenia". Retrieved 2011-08-21. 
  9. ^ Kane, J. M.; d'Souza, D. C.; Patkar, A. A.; Youakim, J. M.; Tiller, J. M.; Yang, R.; Keefe, R. S. E. (2010). "Armodafinil as Adjunctive Therapy in Adults with Cognitive Deficits Associated with Schizophrenia". The Journal of Clinical Psychiatry. 71 (11): 1475–1481. doi:10.4088/JCP.09m05950gry. PMID 20816042. 
  10. ^ Pollack, Andrew (January 6, 2010). "A Drug's Second Act: Battling Jet Lag". The New York Times. Retrieved 2010-03-30. 
  11. ^ Pollack, Andrew (March 29, 2010). "Regulators Reject a Drug Maker's Plan to Use Its Alertness Pill to Overcome Jet Lag". The New York Times. Retrieved 2010-03-30. 
  12. ^ http://www.rxlist.com/nuvigil-drug/side-effects-interactions.htm
  13. ^ http://armodexperiment.com/?s=dry+mouth

External links[edit]

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