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Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives

Analysis of Data from Three Randomized, Single-Dose, Pharmacokinetic Studies


Background and objective: Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations.

Methods: Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50,100,200,250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed.

Results: Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of∼13 hours, with similar mean maximum plasma drug concentration (Cmax) and median time to Cmax values. After reaching Cmax, plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and AUC from time zero to infinity (AUC∞) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis.

Conclusions: Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.

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This analysis was sponsored by Cephalon, Inc., Frazer, PA, USA. All authors are employees of Cephalon, Inc. The authors wish to acknowledge Ryan Dammerman, MD, PhD (Cephalon, Inc. employee) for his contribution to the medical content of this paper and Thomson Reuters (Horsham, PA, USA) and Virginia Schobel (Cephalon, Inc. employee) for their editorial assistance. The authors would also like to acknowledge the work of the study investigators: Stephen Freestone, MD, Inveresk Research, Tranent, Scotland (study 1); Dennis Swearingen, MD, MDS Pharma Services, Phoenix, AZ, USA (study 2); and Krishna K. Talluri, MD, PPD Pharmaco, Inc., Morrisville, NC, USA (study 3).

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Correspondence to Mona Darwish.

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Darwish, M., Kirby, M., Hellriegel, E.T. et al. Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives. Clin. Drug Investig. 29, 613–623 (2009).

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  • Modafinil
  • Obstructive Sleep Apnoea
  • Plasma Drug Concentration
  • Narcolepsy
  • Armodafinil