Daytime pharmacodynamic and pharmacokinetic evaluation of low-dose sublingual transmucosal zolpidem hemitartrate

Abstract

Objectives: Buffered low-dose sublingual transmucosal zolpidem lozenge hemitartrate (ST zolpidem) is being developed for the treatment of middle-of-the-night insomnia. The objective of this double-blind placebo-controlled cross-over study (n = 24) was to evaluate the pharmacokinetics (PK) and daytime-sedative profile of 1.0, 1.75, and 3.5 mg dose of the formulation.

Methods: Daytime sedation was measured pre-dose and up to 5 h post-dose objectively by the Digit Symbol Substitution Test (DSST) and subjectively using the Visual Analog Scale (VAS). Blood samples for PK assessment was collected pre-dose and up to 12 h post-dose.

Results: The 1.75 and 3.5 mg, but not the 1 mg, ST zolpidem produced significant sedation versus placebo within 20 min of dosing which lasted for up to 3 h. Zolpidem from the formulation was rapidly absorbed and reached maximum plasma concentrations within 38 min of dosing, however the half-life was independent of the dose and side effects were consistent with the known pharmacology of the drug.

Conclusions: ST zolpidem produced rapid, short duration of sedation and the effect was consistent with its PK profile. This novel low-dose formulation of zolpidem may provide clinicians and patients with a prn option for the management of sleep maintenance insomnia.

Figure 1

Mean change over baseline in DSST scores

Figure 2

Mean±SEM 1 h effect areas for changes over baseline in DSST scores

Figure 3

Mean change over baseline in scores of self-rated sedation on 100mm VAS

Figure 4

Plasma concentration–time profiles of zolpidem following ST zolpidem administration