Clinical Pharmacokinetics

, Volume 42, Issue 2, pp 123–137 | Cite as

Clinical Pharmacokinetic Profile of Modafinil

  • Philmore RobertsonJrEmail author
  • Edward T. Hellriegel
Review Article Drug Disposition


Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain.

After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2–4 hours after administration and pharmacokinetic steady state within 2–4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12–15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer.

Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging.

Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil.

In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.


Methylphenidate Modafinil Triazolam Narcolepsy Ethinylestradiol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are employees of Cephalon, Inc., which markets modafinil as PROVIGIL®.


  1. 1.
    Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther 1997; 283: 757–69PubMedGoogle Scholar
  2. 2.
    Ferraro L, Antonelli T, O’Connor WT, et al. Modafinil: an anti-narcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry 1997; 42: 1181–3PubMedCrossRefGoogle Scholar
  3. 3.
    Simon P, Hemet C, Ramassamy C, et al. Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice. Eur Neuropsychopharmacol 1995; 5: 509–14PubMedGoogle Scholar
  4. 4.
    De Sereville JE, Boer C, Rambert FA, et al. Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: in vivo voltammetry studies. Neuropharmacology 1994; 33: 755–61PubMedCrossRefGoogle Scholar
  5. 5.
    Mignot E, Nishino S, Guilleminault C, et al. Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 1994; 17: 436–7PubMedGoogle Scholar
  6. 6.
    Lin JS, Roussel B, Akaoka H, et al. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 1992; 591: 319–26PubMedCrossRefGoogle Scholar
  7. 7.
    Akaoka H, Roussel B, Lin JS, et al. Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity. Neurosci Lett 1991; 123: 20–2PubMedCrossRefGoogle Scholar
  8. 8.
    Engber TM, Dennis SA, Jones BE, et al. Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine. Neuroscience 1998; 87: 905–11PubMedCrossRefGoogle Scholar
  9. 9.
    Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci U S A 1996; 93: 14128–33PubMedCrossRefGoogle Scholar
  10. 10.
    Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 2000; 20: 8620–8PubMedGoogle Scholar
  11. 11.
    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; 39: 281–8PubMedGoogle Scholar
  12. 12.
    Wong YN, King SP, Laughton WB, et al. Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers. J Clin Pharmacol 1998; 38: 276–82PubMedGoogle Scholar
  13. 13.
    US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000; 54: 1166–75CrossRefGoogle Scholar
  14. 14.
    US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998; 43: 88–97CrossRefGoogle Scholar
  15. 15.
    Broughton RJ, Fleming JA, George CF, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997; 49: 444–51PubMedCrossRefGoogle Scholar
  16. 16.
    Boivin DB, Montplaisir J, Petit D, et al. Effects of modafinil on symptomatology of human narcolepsy. Clin Neuropharmacol 1993; 16: 46–53PubMedCrossRefGoogle Scholar
  17. 17.
    Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12: 695–700PubMedCrossRefGoogle Scholar
  18. 18.
    McClellan KJ, Spencer CM. Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 1998; 9: 311–24CrossRefGoogle Scholar
  19. 19.
    Gorman SH. Determination of the d- and 1-enantiomers of modafinil in human plasma utilizing liquid-liquid extraction and high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1999; 730: 1–7PubMedCrossRefGoogle Scholar
  20. 20.
    Gorman SH. Determination of modafinil, modafinil acid, and modafinil sulfone in human plasma utilizing liquid-liquid extraction and high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 767: 269–76PubMedCrossRefGoogle Scholar
  21. 21.
    Burnat P, Robles F, Do B. High-performance liquid Chromatographic determination of modafinil and its two metabolites in human plasma using solid-phase extraction. J Chromatogr B Biomed Sci Appl 1998; 706: 295–304PubMedCrossRefGoogle Scholar
  22. 22.
    Moachon G, Matinier D. Simultaneous determination of modafinil and its acid metabolite by high-performance liquid chromatography in human plasma. J Chromatogr B Biomed Appl 1994; 654: 91–6PubMedCrossRefGoogle Scholar
  23. 23.
    Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982Google Scholar
  24. 24.
    Moachon G, Kanmacher I, Clenet M, et al. Pharmacokinetic profile of modafinil. Drugs Today 1996; 32: 327–37Google Scholar
  25. 25.
    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; 39: 30–40PubMedCrossRefGoogle Scholar
  26. 26.
    Wong YN, Wang L, Hartman L, et al. Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol 1998; 38: 971–8PubMedGoogle Scholar
  27. 27.
    Hellriegel ET, Arora S, Nelson M, et al. Steady-state pharmacokinetics and tolerability of modafinil given alone or in combination with methylphenidate in healthy volunteers. J Clin Pharmacol 2001; 41: 895–904PubMedCrossRefGoogle Scholar
  28. 28.
    Hellriegel ET, Arora S, Nelson M, et al. Steady-state pharmacokinetics and tolerability of modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol 2002; 42: 450–60PubMedCrossRefGoogle Scholar
  29. 29.
    Robertson P, Hellriegel ET, Arora S, et al. Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. J Clin Pharmacol 2002; 42: 205–14PubMedCrossRefGoogle Scholar
  30. 30.
    Robertson P, Hellriegel ET, Arora S, et al. Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther 2002; 71: 46–56PubMedCrossRefGoogle Scholar
  31. 31.
    Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19: 359–89PubMedCrossRefGoogle Scholar
  32. 32.
    Schmucker DL. Aging and drug disposition: an update. Pharmacol Rev 1985; 37: 133–48PubMedGoogle Scholar
  33. 33.
    Robertson P, DeCory HH, Madan A, et al. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos 2000; 28: 664–71PubMedGoogle Scholar
  34. 34.
    Le Cacheux P, Charasse C, Mourtada R, et al. Gelineau syndrome in a patient with renal transplantation: evidence of cyclosporine-modafinil interaction [letter]. Presse Med 1997; 26: 466PubMedGoogle Scholar
  35. 35.
    Grözinger M, Hartter S, Hiemke C, et al. Interaction of modafinil and clomipramine as comedication in a narcoleptic patient. Clin Neuropharmacol 1998; 21: 127–9PubMedGoogle Scholar

Copyright information

© Adis International Limited 2003

Authors and Affiliations

  1. 1.Department of Drug Safety and DispositionCephalon, Inc.West ChesterUSA

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