Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects

Abstract

What is already known about this subject: Body sway increases in older adults and may lead to an increase in the risk of falling. The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next-day falls as well as drowsiness. The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed.

What this study adds: This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments. Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem. Compared with placebo, neither gaboxadol nor zolpidem impaired attention/information-processing ability as assessed by critical flicker fusion.

Aims: To evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects.

Methods: Subjects (17 women, seven men) aged 65-75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three-period, randomized, double-blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single-blind treatment period. Adverse events were recorded throughout the study.

Results: The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol t(max) was 2 h, t((1/2)) was 1.7 h, AUC(0-infinity) was 430 ng.h ml(-1) and C(max) was 139 ng ml(-1). At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo.

Conclusions: A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.

Figure 1

Representative scatter plot of the centre of pressure (COP) data from an ‘eyes closed’ condition in the body sway test. Scatter plot demonstrates displacement of the COP on the abscissa and ordinate relative to the platform (cm). The plot is overlaid with the 95th percentile ellipse and represents the area of the 95% confidence ellipse enclosing the COP (A95, cm²)

Figure 2

Mean plasma concentrations of gaboxadol 10 mg in healthy elderly men and women at bedtime. The inset shows the data plotted on a logarithmic scale for the ordinate; the abscissa is the same as the main graph (time, in h). Men (n = 7) (); Women (n = 15) (○); Overall (n = 22) (▾)

Figure 3

Geometric mean fold change from baseline (95% CI) for body sway area after 10 mg gaboxadol, 5 mg zolpidem, and placebo, and P-values for treatment ratios of fold change from baseline for (a) ‘eyes open’ and (b) ‘eyes closed’. A value >1 indicates increased body sway relative to baseline. ***P < 0.001; **P < 0.01; *P < 0.05 active drug vs. placebo; †P < 0.001 gaboxadol vs. zolpidem; §P < 0.01 gaboxadol vs. zolpidem. Gaboxadol 10 mg (•); Zolpidem 5 mg (▴); Placebo ()