Armodafinil

Adverse effects

In placebo-controlled studies, the most commonly observed side effects were headache, xerostomia (dry mouth), nausea, dizziness, and insomnia. Possible side effects also include depression, anxiety, hallucinations, euphoria, extreme increase in activity and talking, anorexia, tremor, thirst, rash, suicidal thoughts, and aggression. Symptoms of an overdose on armodafinil include trouble sleeping, restlessness, confusion, disorientation, feeling excited, mania, hallucinations, nausea, diarrhea, severely increased or decreased heart beat, chest pain, and increased blood pressure. Serious rashes can develop in rare cases, and require immediate medical attention due to the possibility of Stevens–Johnson syndrome, or other hypersensitivities to armodafinil.

Misuse potential

Armodafinil has a low misuse potential similar to modafinil.

Interactions

Hypertensive crises have been reported when armodafinil has been taken with monoamine oxidase inhibitors (MAOIs) like tranylcypromine.

Pharmacology

Pharmacodynamics

The mechanism of action of armodafinil is not fully known. It 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 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 DAT, modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. The wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, α-methyl-p-tyrosine (AMPT), 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, 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. 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]."

Armodafinil (R-(−)-modafinil) has pharmacological properties almost identical to those of modafinil, a mixture of armodafinil and esmodafinil ((S)-(+)-modafinil). The (R)- and (S)-enantiomers have similar pharmacological action in animals. In humans however, armodafinil has a lower therapeutic dose range than modafinil, suggesting greater clinical potency, and also has a longer duration.

Like modafinil, armodafinil is an inhibitor and/or inducer of certain cytochrome P450 enzymes. It moderately induces CYP3A4 and moderately inhibits CYP2C19. In contrast to modafinil, however, armodafinil does not induce CYP1A2.

Pharmacokinetics

Absorption

Armodafinil is rapidly absorbed with oral administration. The oral bioavailability of armodafinil is not known as the drug is water-insoluble and hence cannot be administered intravenously for comparison studies. In any case, the bioavailability of modafinil is estimated to be between 45% and 65% based on excretion studies. The time to peak levels of armodafinil when fasted has been reported be median 1.5 to 2 hours (range 0.5–6 hours). In one study however, the time to peak levels was median 6.5 hours (range 3–11 hours). Taking armodafinil with food does not affect its overall bioavailability but has been found to delay time to peak levels by 2 to 4 hours. As a result, food may affect the onset and duration of armodafinil.

Armodafinil shows linear or dose-proportional pharmacokinetics over a dose range of 50 to 400 mg orally. Steady state levels are reached within 3 to 7 days of once-daily continuous administration. Steady-state levels of armodafinil are 1.8-fold higher than after a single dose. No time-dependent changes in armodafinil's pharmacokinetics have been observed over 12 weeks of administration.

Modafinil and armodafinil show similar peak levels and times to peak levels in directly comparative studies. Due to armodafinil having a longer elimination half-life than esmodafinil however, armodafinil constitutes 90% of modafinil levels at steady state with modafinil therapy.

Distribution

The apparent volume of distribution of armodafinil is approximately 42 L or 0.5 to 0.8 L/kg body weight. Data on the plasma protein binding of armodafinil are not available, but modafinil is known to be 60% bound to plasma proteins, with it being bound primarily to albumin. Both armodafinil and esmodafinil are known to be P-glycoprotein substrates, but the clinical significance of this is unknown.

Metabolism

The metabolism of armodafinil is via hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation. Subsequently, its hydroxylated metabolites undergo conjugation via glucuronidation. The major metabolic pathway is amide hydrolysis into armodafinil acid, with the second most major pathway being sulfone formation into modafinil sulfone. The sulfonation of armodafinil is catalyzed by the cytochrome P450 enzymes CYP3A4 and CYP3A5, whereas hydroxylation is mediated by CYP2C9. Two armodafinil metabolites, armodafinil acid and modafinil sulfone, reach appreciable concentrations in the circulation. Both of these metabolites have been said to be pharmacologically inactive. However, modafinil sulfone is known to produce anticonvulsant effects in animals, a property that it shares with modafinil.

Elimination

More appears to be known about the elimination of modafinil than armodafinil. Modafinil is eliminated mainly via metabolism (90%), with less than 10% of a dose being excreted unchanged in urine. Modafinil, given as a single dose in radiolabeled form, is excreted 80% in urine and 1% in feces by 11 days post-administration. Urinary recovery as the major metabolite modafinil acid has been found to be 35 to 51% of a dose.

The apparent terminal elimination half-life of armodafinil is approximately 15 hours, with a range of 10 to 17 hours in different studies. Its oral clearance at steady state is approximately 33 mL/min.

The individual enantiomers of modafinil, armodafinil and esmodafinil, have substantially different pharmacokinetics due to differing elimination profiles. Both armodafinil and esmodafinil are eliminated in a monophasic manner. However, armodafinil has a half-life of 10 to 17 hours, while esmodafinil has a half-life of 3 to 5 hours (3–4 times shorter). Consequently, modafinil, a racemic mixture (1:1) of armodafinil and esmodafinil, has a biphasic elimination profile, with esmodafinil being eliminated much more rapidly than armodafinil. Armodafinil and modafinil have shown virtually identical elimination half-lives of approximately 12 to 16 hours in directly comparative studies. However, due to the biphasic elimination profile of modafinil, armodafinil shows higher levels than modafinil from 4 to 6 hours after administration and about 40% higher area-under-the-curve (AUC) levels than modafinil. Moreover, armodafinil showed 42% lower peak-to-trough variation than modafinil with once-daily administration at steady state. Because of the preceding, armodafinil has a longer duration and more stable levels than modafinil.

Chemistry

Armodafinil, or (R)-(–)-modafinil, is the enantiopure (R)-(–)-enantiomer of the racemic mixture modafinil, while esmodafinil is the (S)-(+)-enantiomer.

Synthesis

The chemical synthesis of armodafinil has been described.

Analogues

A number of analogues of armodafinil are known, including adrafinil, flmodafinil, fladrafinil, and others.

History

Adrafinil was discovered by the pharmaceutical company Lafon in France in 1974. Subsequently, it was found that adrafinil is a prodrug of modafinil in 1976. Modafinil was then patented in 1979. Adrafinil was introduced for medical use in France in 1981. It was registered for medical use in France in 1992 and became available in 1994. Cephalin leased the rights for modafinil in the United States in 1993 and eventually purchased Lafon in 2001. Modafinil was approved for medical use in the United States in 1998.

Armodafinil was patented in 1987. It was introduced for medical use in the United States in 2007. Teva Pharmaceuticals took over Cephalon and all of its products, including modafinil and armodafinil, in 2011.

Modafinil was originally thought to act as an α₁-adrenergic receptor agonist, but this hypothesis was later found to be incorrect. Subsequently, modafinil was identified as an atypical dopamine reuptake inhibitor (DRI). Modafinil and armodafinil were respectively shown to occupy the dopamine transporter (DAT) and increase brain dopamine levels at clinical therapeutic doses in humans in 2009 and 2010, which is said to have put an end to the debate about their mechanism of action, though not excluding the possibility of other actions also being involved in its effects.

Society and culture

Brand names

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

• Acronite (by Consern Pharma): India
• Armoda: ACI Pharmaceuticals (Symbiota), Bangladesh
• Armod: India (by Emcure Pharmaceuticals Ltd)
• Artvigil: India (by HAB Pharma)
• Neoresotyl: Chile, Colombia
• Nuvigil: USA, Chile, Ukraine, Israel, Mexico, Australia
• R-Modawake: India
• Waklert: India (by Sun Pharma)
• Modavital: El Salvador (Farmaceutica INHOSPI (by Laboratorios Marceli)
• Nodement: Syrian Arab republic (by hama pharma)
• Armowake: Egypt (by EVA Pharma)

Legal status

In Australia and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy. Schedule 4 is defined as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."

Romania

As of 2021, new laws do not directly include Armodafinil as a doping agent, but they do include Modafinil, as Armodafinil is an enantiomer of Modafinil it will show up on lab tests, but it can be debated if it is or not the same substance.

New laws state that simple possession is not a criminal offence and is punished with a fine and confiscation. Importing into Romania and exporting from Romania of the substance, without a valid medical prescription, is a criminal offence and is punished with jail time between two and seven years.

Research

Besides hypersomnia, armodafinil was under development for the treatment of fatigue, bipolar depression, and schizophrenia. Nonetheless, development for these indications was discontinued. The drug reached phase 3 clinical trials for treatment of fatigue prior to the discontinuation of its development for this use in January 2024. Aside from the preceding indications, armodafinil is currently under development for the treatment of eating disorders and, as of January 2024, is in phase 3 trials for this use.