|Systematic (IUPAC) name|
|Metabolism||Hepatic, including CYP3A4 and other pathways|
|Excretion||Urine (as metabolites)|
|(what is this?)|
Armodafinil (Nuvigil) is the enantiopure of the vigilance-promoting drug, or eugeroic, Modafinil (Provigil). It consists of just the (−)-(R)-enantiomer of the racemic Modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. and was approved by the U.S. Food and Drug Administration (FDA) in June 2007.
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.
Mechanism of action
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 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 DAT, 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-thyrosine, a dopamine synthesis inhibitor, 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, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self administration in monkeys previously trained to administer cocaine; modafinil was also partially discriminated as stimulant like. Modafinil has been shown to have a similar abuse potential to methylphenidate in an inpatient study with experienced drug users. Modafinil produced psychoactive and euphoric effects consistent with other CNS stimulants. AN independent study in which patients were administered modafinil, methylphenidate, and a placebo found that modafinil produces the same level of extracellular dopamine produced by methylphenidate.
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 C max 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.
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 t max is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.
Armodafinil is currently FDA-approved to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder. 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.
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. 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.
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. However, a study published later that year showed that schizophrenic patients treated with armodafinil showed fewer of the negative symptoms of schizophrenia.
In placebo-controlled studies, the most commonly observed side effects were headache, 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, severly increased or decreased heart beat, chest pain, and increased blood pressure.
Armodafinil is sold under a wide variety of brand names world wide.
- R-Modawake - India
- Artvigil - India
- Waklert - India (discontinued Armod, Armod)
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