Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers

• Published in: Clinical pharmacology and therapeutics Vol. 71; no. 1; p. 46
• Main Authors: Robertson, Jr, Philmore, Hellriegel, Edward T, Arora, Sanjay, Nelson, Michael
• Format: Journal Article
• Language: English
• Published: United States 01.01.2002
• Subjects: Adult; Area Under Curve; Benzhydryl Compounds - adverse effects; Benzhydryl Compounds - pharmacology; Biomarkers; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - pharmacology; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions; Estradiol Congeners - adverse effects; Estradiol Congeners - pharmacokinetics; Ethinyl Estradiol - adverse effects; Ethinyl Estradiol - pharmacokinetics; Female; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - pharmacokinetics; Mass Spectrometry; Mixed Function Oxygenases - metabolism; Modafinil; Single-Blind Method; Spectrophotometry, Ultraviolet; Triazolam - adverse effects; Triazolam - pharmacokinetics
• ISSN: 0009-9236
• DOI: 10.1067/mcp.2002.121217

Modafinil has been reported to produce a concentration-related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes. Our objective was to determine whether the pharmacokinetics of steady-state ethinyl estradiol (INN, ethinylestradiol) and single-dose triazolam were altered after 4 weeks of modafinil treatment in volunteers. This was a placebo-controlled, single-blind, single-period study in 41 female subjects who were receiving long-term treatment with an oral contraceptive that contained ethinyl estradiol (0.035 mg) and norgestimate (0.180-0.250 mg). Pharmacokinetic profiles for ethinyl estradiol and for a single oral dose of triazolam (0.125 mg) were obtained the day before initiation of treatment with modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo (28 days). A second dose of triazolam was administered with the final dose of modafinil, and pharmacokinetic profiling was repeated. The modafinil treatment group had a marked decrease in maximum observed plasma concentrations and areas under the plasma concentration-time curve for triazolam relative to placebo, with a much smaller decrease in these parameters for ethinyl estradiol. The half-life of triazolam was also decreased, but the half-life of ethinyl estradiol did not appear to be affected by treatment with modafinil. Modafinil induced CYP3A4/5 activity in humans in vivo, suggesting that there is potential for metabolic drug-drug interactions between modafinil and substrates of CYP3A4/5. However, the induction appeared to be more gastrointestinal than hepatic in nature. Therefore significant metabolic drug-drug interactions are most likely to occur with compounds (such as triazolam) that undergo significant gastrointestinal CYP3A4/5-mediated first-pass metabolism.