Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2002) 71, 46–56; doi: 10.1067/mcp.2002.121217
Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers*
Philmore Robertson Jr PhD1, Edward T. Hellriegel PhD1, Sanjay Arora PhD1 and Michael Nelson BA1
1Departments of Drug Disposition, Biostatistics, and Medical Affairs, Cephalon, Inc.
Correspondence: Philmore Robertson, Jr, PhD, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380. E-mail: proberts@cephalon.com
*Supported by Cephalon, Inc, West Chester, Pa.
Received 26 June 2001; Accepted 17 October 2001.
Abstract
Background: Modafinil has been reported to produce a concentration-related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes.
Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
