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.

This is a preview of subscription content, access via your institution.

Table I
Table II
Fig. 1
Table III
Table IV


  1. 1.

    Hirshkowitz M, Black JE, Wesnes K, et al. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med 2007 Mar; 101(3): 616–27

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Roth T, White D, Schmidt-Nowara W, et al. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther 2006 May; 28(5): 689–706

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Czeisler CA, Walsh JK, Wesnes KA, et al. A randomized clinical trial of armodafinil for the treatment of excessive sleepiness associated with shift-work disorder. Mayo Clin Proc. In press

  4. 4.

    Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin 2006 Apr; 22(4): 761–74

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Data on file, Cephalon, Inc., Frazer, PA, USA: Jul 2009

  6. 6.

    Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999 Jan; 39(1): 30–40

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Wong YN, King SP, Simcoe D, et al. Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol 1999 Mar; 39(3): 281–8

    PubMed  CAS  Google Scholar 

  8. 8.

    Robertson Jr P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet 2003; 42(2): 123–37

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Darwish M, Kirby M, Hellriegel ET, et al. Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies. Clin Drug Investig 2009; 29(2): 87–100

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Darwish M, Kirby M, Hellriegel ET. Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration. Clin Drug Investig 2009; 29 (9): ((To come))

  11. 11.

    Schwartz JR, Nelson MT, Schwartz ER, et al. Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness. Clin Neuropharmacol 2004 Mar–Apr; 27(2): 74–9

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Schwartz JR, Feldman NT, Bogan RK, et al. Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy. Clin Neuropharmacol 2003 Sep–Oct; 26(5): 252–7

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Schwartz JR, Feldman NT, Bogan RK. Dose effects of modafinil in sustaining wakefulness in narcolepsy patients with residual evening sleepiness. J Neuropsychiatry Clin Neurosci 2005 Summer; 17(3): 405–12

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin 2006 Jan; 22(1): 159–67

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    International Conference on Harmonisation 1996. Guideline for good clinical practice, E6(R1). International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use; 1996 [online]. Available from URL: pdfs/human/ich/013595en.pdf [Accessed 2009 Jul 23]

  16. 16.

    Roth T, Rippon GA, Arora S. Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea. Sleep Breath 2008 Mar; 12(1): 53–62

    PubMed  Article  Google Scholar 

Download references


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).

Author information



Corresponding author

Correspondence to Mona Darwish.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation


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