Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects.
OBJECTIVE
Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration.


METHODS
A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18).


RESULTS
Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil.


CONCLUSIONS
At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.
Darwish
Mona
M
Clinical Pharmacology Department, Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
Kirby
Mary
M
Hellriegel
Edward T
ET
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D010919:Placebos; D000077408:Modafinil