COMPARATIVE KINETICS AND DYNAMICS OF ZALEPLON, ZOLPIDEM, AND PLACEBO

Purpose: This study evaluated the relationship of dose, plasma concent ration, and time to the pharmacodynamics of zaleplon and zolpidem, 2 s tructurally distinct benzodiazepine receptor agonists. Method: Ten hea lthy male volunteers received single oral doses of placebo, 10 mg zale plon, 20 mg zaleplon, 10 mg zolpidem, and 20 mg zolpidem in a double-b lind, 5-condition crossover study, with 48 hours elapsing between tria ls. Plasma drug concentrations and pharmacodynamic effects were measur ed during the 8 to 24 hours after administration. Results: Kinetics of zaleplon and zolpidem were not significantly related to dose. However , zaleplon had more rapid elimination (apparent elimination half-life [t(1/2)] of I hour) and higher apparent oral clearance (approximately 4300 mL/min) than zolpidem (t(1/2), 2.0 to 2.2 hours; apparent oral cl earance, 340 to 380 mL/min). Active treatments produced pharmacodynami c effects consistent with benzodiazepine agonist activity: self- and o bserver-rated sedation, impairment of digit symbol substitution test ( DSST) performance, impaired memory, and increased electroencephalograp hic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 1 0 mg zolpidem < 20 mg zolpidem; on a number of measures, 20 mg zaleplo n was comparable to 10 mg zolpidem. Quantitative effects of zolpidem 2 0 mg far exceeded those of other treatments. Dynamic effects of both d rugs were significantly related to plasma concentration. Conclusions: Benzodiazepine agonist effects of zaleplon and zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic do se (10 mg of either drug), agonist effects of zolpidem exceeded those of zaleplon.