Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects

Clin Pharmacokinet. 2008;47(1):61-74. doi: 10.2165/00003088-200847010-00006.


Background and objective: Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate.

Methods: Healthy men and nonpregnant women aged 18-45 years with a body mass index of </=30 kg/m(2) each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum observed drug plasma concentration (C(max)). Safety and tolerability were also assessed.

Results: A total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the C(max) or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the C(max) of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events.

Conclusions: Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / pharmacokinetics*
  • Caffeine / administration & dosage
  • Caffeine / metabolism
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacokinetics
  • Clinical Trials as Topic
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Male
  • Metabolic Clearance Rate / drug effects
  • Midazolam / administration & dosage
  • Midazolam / metabolism
  • Mixed Function Oxygenases / metabolism*
  • Modafinil
  • Pharmaceutical Preparations / administration & dosage
  • Pharmaceutical Preparations / metabolism*
  • Theophylline / administration & dosage
  • Theophylline / metabolism


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Pharmaceutical Preparations
  • Caffeine
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • 1,7-dimethylxanthine
  • Modafinil
  • Midazolam