A Placebo‐Controlled Evaluation of Single, Escalating Doses of CL 284,846, a Non‐Benzodiazepine Hypnotic

Abstract

This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

Zaleplon pharmacokinetics and absolute bioavailability

“…Zaleplon's t 1/2 was approximately 1 h following both oral and iv administration. The pharmacokinetic results observed for zaleplon following oral administration in the present study are similar to those observed previously [3].…”

“…Plasma samples were assayed for determination of zaleplon concentrations by a validated high performance liquid chromatography method with fluorescence detection [3]. Standard curves were linear over the zaleplon plasma concentration range of 0.55-300 ng/mL, with a sensitivity of 0.5 ng/mL.…”

“…In humans, single oral doses of zaleplon are quickly absorbed and eliminated, with a time to peak concentration (t max ) and an elimination halflife (t 1/2 ) of approximately 1 h [3]. Peak plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) both exhibit linear dose proportionality at doses up to 60 mg [3], well above the 10 mg therapeutic dose [4][5][6].…”

Electroencephalographic Properties of Zaleplon, a Non-Benzodiazepine Sedative/Hypnotic, in Rats

“…Thus, it is suggested that the hypnotic effect of zaleplon is characterized by rapid onset, as compared with that of triazolam and the other hypnotics tested. Elimination of zaleplon in rats was rapid with a terminal half-life of approximately 1 h, and absorption was rapid, similar to what has been observed in humans (5,9). Thus, the EEG recording and spectral analysis study in rats support the pharmacokinetics characterized by rapid absorption of zaleplon, and the rapid sleep onset of zaleplon may be solely due to rapid absorption.…”

“…The elimination half-life of zaleplon is approximately 1 h, regardless of dose and the absorption is rapid (9). Therefore, as the hypnotic action of zaleplon can be characterized by rapid onset and short duration of action, it has been suggested that zaleplon should be classified as an ultra-short-acting sedative / hypnotic agent, and it may be used for insomnia in patients whose main difficulty is in falling asleep.…”