OBJECTIVE This study compared the pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic (PK/PD) profile of zaleplon, a new pyrazolopyrimidine hypnotic, with those of zolpidem and placebo. METHODS This was a double-blind, 5-period crossover study in which healthy volunteers with no history of sleeping disorder were randomized to 10- or 20-mg oral doses of zaleplon, 10- or 20-mg oral doses of zolpidem, or placebo. The pharmacokinetic characteristics of the active drugs were estimated using a noncompartmental method and NONMEM. Pharmacodynamic characteristics were determined using psychophysical tests, including measures of sedation, mood, mental and motor speed, and recent and remote recall. Results of these tests were used to compare the drugs' relative PK/PD profiles. RESULTS Ten healthy male and female volunteers, aged 23 to 31 years, took part in the study. The apparent elimination half-life of zaleplon (60.1+/-8.9 min) was significantly shorter than that of zolpidem (124.5+/-37.9 min) (P < 0.001). Zaleplon produced less sedation than zolpidem at the 2 doses studied (P < 0.001). The sedation scores of the zaleplon groups returned to baseline in less time than those of the zolpidem groups (4 vs 8 hours; P < 0.05). Zaleplon had no effect on recent or remote recall, whereas zolpidem had a significant effect on both measures (P < 0.05). CONCLUSIONS In this study in 10 young, healthy volunteers, zaleplon was eliminated more rapidly, produced no memory loss, and caused less sedation than zolpidem at the same doses.