Pharmacokinetic determinants of hypnotic drug action: The art and science of controlling release

Pharmacokinetic properties of hypnotic drugs are important determinants of onset, intensity and duration of clinical action, as well as the occurrence of side effects (such as excessive night-time sedation or respiratory depression and residual next-day sedation). Based largely upon safety considerations, the pattern of hypnotic drug use has shifted away from long half-life compounds in favor of drugs with a short half-life. These include the benzodiazepine triazolam, and the nonbenzodiazepines zolpidem, zaleplan, and zopiclone. Zolpidem is the most widely prescribed of these. Zolpidem is rapidly absorbed (mean absorption half-life of 30 min), providing rapid onset of action and proven efficacy for sleep-onset latency, and is rapidly eliminated (mean half-life of 2.7 h), thereby reducing the likelihood of residual effects. Zolpidem therefore promotes sleep and sleep initiation but may not act for long enough to sustain sleep throughout the night. The attainment of an ideal profile, with a defined duration of action and an appropriate continuous-release profile, does not seem to be possible by simply adjusting the dosage or absorption rate of a single-release preparation. Modified-release preparations offer the possibility of customizing the plasma concentration curve over time. The modified-release formulation of zolpidem shows a more sustained effect compared with immediate-release zolpidem, providing both a rapid onset of action as well as maintained sedative effects over 3–6 h post-dose and few residual effects.