Mechanism of Action and Pharmacology
The precise mechanism(s) through which armodafinil (R-enantiomer) or modafinil (mixture of R- and S-enantiomers) promote wakefulness is unknown. Both armodafinil and modafinil have shown similar pharmacological properties in nonclinical animal and in vitro studies, to the extent tested.
At pharmacologically relevant concentrations, armodafinil does not bind to or inhibit several receptors and enzymes potentially relevant for sleep/wake regulation, including those for serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, orexin-1, orphanin, PACAP or benzodiazepines, or transporters for GABA, serotonin, norepinephrine, and choline or phosphodiesterase VI, COMT, GABA transaminase, and tyrosine hydroxylase. Modafinil does not inhibit the activity of MAO-B or phosphodiesterases II-IV.
Modafinil-induced wakefulness can be attenuated by the Î±1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to alpha-adrenergic agonists such as the rat vas deferens preparation.
Armodafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, both armodafinil and modafinil bind to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. 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-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil.
Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. 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 self-administer cocaine; modafinil was also partially discriminated as stimulant-like.
Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds.
The active component of NUVIGIL is armodafinil, which is the longer-lived enantiomer of modafinil. NUVIGIL exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for NUVIGIL was reached within 7 days of dosing. At steady state, the systemic exposure for NUVIGIL is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the pure R-enantiomer following administration of 50 mg NUVIGIL or 100 mg PROVIGIL® (modafinil) are nearly superimposable.
NUVIGIL 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 NUVIGIL is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma levels later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL.
NUVIGIL has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of NUVIGIL with highly protein-bound drugs is considered to be minimal.
In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).
Data specific to NUVIGIL disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces).
After oral administration of NUVIGIL, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of NUVIGIL is approximately 33 mL/min.
The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications.
In vitro data demonstrated that armodafinil shows a weak inductive response for CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein.
Chronic administration of NUVIGIL at 250 mg reduced the systemic exposure to midazolam by 32% and 17% after single oral (5 mg) and intravenous (2 mg) doses, respectively, suggesting that administration of NUVIGIL moderately induces CYP3A activity. Drugs that are substrates for CYP3A4/5, such as cyclosporine, may require dosage adjustment. (See PRECAUTIONS, Drug Interactions).
Chronic administration of NUVIGIL at 250 mg did not affect the pharmacokinetics of caffeine (200 mg), a probe substrate for CYP1A2 activity.
Coadministration of a single 400-mg dose of NUVIGIL with omeprazole (40 mg) increased systemic exposure to omeprazole by approximately 40%, indicating that armodafinil moderately inhibits CYP2C19 activity. Drugs that are substrates for CYP2C19 may require dosage reduction. (See PRECAUTIONS, Drug Interactions).
Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil.
Data specific to armodafinil in special populations are not available.
A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly (See DOSAGE AND ADMINISTRATION).
The influence of race on the pharmacokinetics of modafinil has not been studied.
In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid was increased 9-fold (See PRECAUTIONS).
The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of NUVIGIL should be reduced in patients with severe hepatic impairment (See PRECAUTIONS and DOSAGE AND ADMINISTRATION).