Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies.
OBJECTIVE
Armodafinil (R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects.


METHODS
Pooled pharmacokinetic data from three separate randomized studies in 119 healthy subjects who received single or multiple (once daily for up to 14 days) oral doses of armodafinil ranging between 50 and 400 mg were analysed. The impact of food on the single-dose pharmacokinetic profile of armodafinil was also assessed in subjects following an overnight fast and after the consumption of a standard fatty meal.


RESULTS
Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50-400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2-4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea.


CONCLUSIONS
In the present analysis, armodafinil exhibited linear pharmacokinetics over the dose range of 50-400 mg. While food affected the rate but not the extent of absorption, peak plasma concentrations were reached in approximately 2 hours when the drug was taken on an empty stomach. With once-daily dosing, steady state appeared to be reached within 7 days. After reaching peak plasma levels, concentrations of armodafinil declined monophasically, with a mean elimination half-life of around 15 hours. Armodafinil was generally well tolerated.
Darwish
Mona
M
Clinical Pharmacology Department, Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
Kirby
Mary
M
Hellriegel
Edward T
ET
Yang
Ronghua
R
Robertson
Philmore
P
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D019518:Postprandial Period; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D000077408:Modafinil