Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study

Clin Ther. 2010 Nov;32(12):2074-87. doi: 10.1016/j.clinthera.2010.11.009.


Background: Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep apnea (OSA). The R-isomer of racemic modafinil has a half-life of approximately15 hours; the S-isomer has a half-life of 4 to 5 hours. The R-and S-isomers are equipotent, producing equivalent pharmacologic activity at equal concentrations.

Objective: The aim of this work was to compare the pharmacokinetic profiles of armodafinil (R-modafinil) and modafinil (racemic mixture with equal quantities of R- and S-isomers) at equal doses in patients with residual excessive sleepiness associated with continuous positive airway pressure-treated OSA.

Methods: This open-label study was conducted at 5 US centers from July 2008 to March 2009. Patients were randomized to 1 of 2 crossover administration sequences, ABCD or BADC, where A was a single armodafinil 200-mg dose, B was a single modafinil 200-mg dose, C was multiple daily modafinil 200-mg doses, and D was multiple daily armodafinil 200-mg doses. During multiple-dose administration, patients received 100 mg once daily for days 1 and 2, and 200 mg once daily for days 3 through 10. The pharmacokinetic parameters of principal interest for assessing the bioequivalence of armodafinil and modafinil were maximum concentration at 7 to 11 hours after dosing and the concentration-versus-time curve for this period. Analysis was performed via achiral high-performance liquid chromatography with ultraviolet detection using blood samples obtained over 72 hours after single-dose administration and over 24 hours after the multiple-dose regimen. For post hoc evaluation of bioequivalence, 90% CI values were also constructed for the geometric mean ratios of armodafinil to modafinil. Tolerability was assessed by the reported adverse events, clinical laboratory testing, vital sign measurements, ECGs, and physical exams.

Results: The study population was 83.3% male (35/42) and 76.2% white (32/42) with a mean (SD) age of 47.0 (8.30) years and a weight range of 66.3 to 127.4 kg. Plasma drug concentration-versus-time curves suggested comparable terminal half-lives (mean [SD] values were 16.5 [4.44] and 14.4 [3.22] hours for armodafinil and modafinil, respectively) but higher systemic exposure with armodafinil than modafinil (mean [SD] AUC(0-∞) values were 108.8 [31.66] and 66.4 [20.06] microg · h/mL for armodafinil and modafinil, respectively), as indicated by the high geometric mean ratios for the AUC (the AUC(0-∞)) ratio after a single dose was 1.64 [95% CI, 1.60-1.68; P < 0.001], and the AUC(0-τ) ratio after multiple doses was 1.69 [95% CI, 1.65-1.72; P < 0.001]) and, to a lesser extent, the ratio of the maximum plasma drug concentration after multiple doses (C(max) ratio = 1.37 [95% CI, 1.33-1.41; P < 0.001]). In addition, the ratios and associated 90% CIs for Cmax (137 [1.341.40]) and AUC(0-τ) (169 [1.66-1.75]) after multiple-dose administration did not meet the US Food and Drug Administration (FDA) criteria for bioequivalence (ie, ratio of geometric means between 80% and 125%). Reported adverse events were mild to moderate in intensity. The most frequently reported adverse events while receiving armodafinil or modafinil were headache (29% and 2%, respectively), diarrhea (12% and 5%), nausea (10% and 2%), and dizziness (10% and 5%).

Conclusions: In this crossover study of patients with treated OSA, overall systemic exposure after armodafinil 200-mg administration was greater than that following modafinil 200-mg administration after both single and multiple doses. The pharmacokinetic profiles of the 2 drugs were notably different and did not meet the FDA criteria for bioequivalence.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Benzhydryl Compounds / pharmacokinetics*
  • Benzhydryl Compounds / pharmacology
  • Benzhydryl Compounds / therapeutic use
  • Central Nervous System Stimulants / pharmacokinetics*
  • Central Nervous System Stimulants / pharmacology
  • Central Nervous System Stimulants / therapeutic use
  • Cross-Over Studies
  • Disorders of Excessive Somnolence / drug therapy*
  • Disorders of Excessive Somnolence / etiology
  • Female
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Modafinil
  • Sleep Apnea, Obstructive / complications*
  • Therapeutic Equivalency


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Modafinil