On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers

Abstract

Study objectives: To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers.

Methods: Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23-78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment.

Results: Mean drug-placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant.

Conclusions: When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated.

Clinical trial registration: clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

Keywords: adults; driving; elderly; hypnotics; lemborexant; orexin antagonist; plasma concentrations; zopiclone.

Figure 1.

Highway driving test. (A) Subjects drive a specially instrumented vehicle for about 1 h over a 100 km primary highway circuit, accompanied by a licensed driving instructor having access to dual controls. The subjects’ task is to drive with a steady lateral position between the delineated boundaries of the slower (right) traffic lane, while maintaining a constant speed of 95 km/h. (B) A camera on top of the car continuously registers the lateral position of the car on the road with respect to the left lane delineation. (C) The standard deviation of lateral position (SDLP in cm) is an index of road tracking error or “weaving.” SDLP scores increase compared with placebo after the use of many sedating drugs including low doses of alcohol. SDLP, standard deviation of lateral position.

Figure 2.

Individual standard deviation of lateral position (SDLP, in cm) differences from placebo, mean and 95% confidence interval by treatment and day, following bedtime administration of lemborexant 2.5, 5, and 10 mg single dose (day 2, n = 32) and repeated doses (day 9, n = 32), and single doses of zopiclone 7.5 mg (days 2 and 9, n = 48). N = 28 on day 2, N = 27 on day 9. Horizontal dashed lines indicate thresholds for impairment (>2.4 cm) and improvement (<−2.4 cm). LEM2.5, lemborexant 2.5 mg; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; SDLP, standard deviation of lateral position; ZOP, zopiclone 7.5 mg.