Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent

The challenge in developing hypnotic agents for the treatment of insomnia is to balance the sedative effect needed at bedtime with the residual sedation on awakening. Zaleplon is a novel pyrazolopyrimidine hypnotic agent that acts as a selective agonist to the brain omega(1) receptor situated on the alpha(1) subunit of the GABA(A) receptor complex. Zaleplon was proven to be an effective hypnotic drug as it consistently and significantly reduced latency to persistent sleep in insomniac patients for doses of 10 mg and above in polysomnography studies. The pharmacodynamic profile of zaleplon on psychomotor performance, actual driving and cognitive function, including memory, was assessed in several randomized, double-blind, placebo-controlled studies in healthy young subjects as well as insomniac patients by using various positive controls (zolpidem, zopiclone, triazolam and flurazepam). The recommended hypnotic dose of zaleplon in young adults (10 mg) produced minimal or no impairment of psychomotor and memory performance even when administered during the night as little as 1 h before waking. No impairment of actual driving was observed when zaleplon 10 mg was administered either at bedtime or in the middle of the night as little as 4 h before waking. Zaleplon 20 mg, twice the recommended dose, generally produced significant impairment of performance and cognitive functions when these functions were measured at the time of peak plasma concentration, i.e. 1 h after dose administration, and no impairment of driving abilities was observed 4 h after a middle-of-the-night administration. In contrast, consistent detrimental residual effects on various aspects of psychomotor and cognitive functions were observed with the therapeutic doses of the various commonly prescribed hypnotic agents used as comparators, e.g. zolpidem 10 mg up to 5 h after dose administration, zopiclone 7.5 mg up to 10 h after, flurazepam 30 mg up to 14 h after and triazolam 0.25 mg up to 6 h after. Also, zolpidem 10 mg and zopiclone 7.5 mg were also shown to significantly impair driving ability the next morning when this was measured 4 h and up to 10 h after dose administration, respectively. The present review shows that zaleplon 10 mg has little or no residual effect when administered in the middle of the night, as late as 1 h before waking, and is devoid of impairment of driving abilities as assessed by actual driving 4 h after dose administration. The lack of clinically significant or minimally statistically significant residual effects of zaleplon even at its peak concentration may be explained by its unique pharmacokinetic (rapid elimination half-life) and pharmacodynamic (low affinity, and specific binding profile to various subunits of the GABA(A)receptor) profiles. These properties allow zaleplon to be used for treatment of symptoms only when they occur, either at bedtime or later in the night, without incurring significant risk of developing next-day impairment of psychomotor and cognitive functioning. Copyright 2001 John Wiley & Sons, Ltd.