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

Darwish, Mona
Kirby, Mary
Hellriegel, Edward T.

¹ Clinical Pharmacology Department, Cephalon, Inc., Frazer, Pennsylvania, USA
² Drug Safety and Disposition Department, Cephalon, Inc., West Chester, Pennsylvania, USA

Correspondence: Dr Mona Darwish, Clinical Pharmacology Department, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355, USA.

E-mail: [email protected]

Clinical Drug Investigation 29(9):p 601-612, September 1, 2009. | DOI: 10.2165/11317740-000000000-00000

Background and 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 (3pm to 7pm after an 8am 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.