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


CONCLUSIONS
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.
Robertson
Philmore
P
Department of Drug Disposition, Cephalon, Inc., West Chester, PA 19380, USA. proberts@cephalon.com
Hellriegel
Edward T
ET
Arora
Sanjay
S
Nelson
Michael
M
D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D015415:Biomarkers; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D045166:Estradiol Congeners / Q000009:adverse effects / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics*; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases / Q000378:metabolism; D000077408:Modafinil; D016037:Single-Blind Method; D013056:Spectrophotometry, Ultraviolet; D014229:Triazolam / Q000009:adverse effects / Q000493:pharmacokinetics*
D001559:Benzhydryl Compounds; D015415:Biomarkers; D000697:Central Nervous System Stimulants; D045166:Estradiol Congeners; D006993:Hypnotics and Sedatives; D014229:Triazolam; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077408:Modafinil