Microsoft word - effect of modafinil on the pharmacokinetics of ethinyl estr

Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy
Clin Pharmacol Ther 2002 Jan;71(1):46-56 (ISSN: 0009-9236)
Robertson P; Hellriegel ET; Arora S; Nelson M
Department of Drug Disposition, Cephalon, Inc., West Chester, PA 19380, USA.
[email protected]
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
CAS Registry / EC
Major Subject Heading(s)
Minor Subject Heading(s)
 Chromatography, High
 28911-01-5 (Triazolam)
 Half-Life
protein, human)
 Mixed Function Oxygenases  EC (nifedipine [metabolism]  Sedatives, Nonbarbiturate [adverse effects]  Single-Blind Method
 Spectrophotometry,
 Spectrum Analysis, Mass
Triazolam [adverse effects]


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