Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

Abstract

IntroductionEsmirtazapine is evaluated as a novel drug for treatment of insomnia.PurposeThe present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control.MethodsTreatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of “weaving”. All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine.ResultsOverall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected.ConclusionIt is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving.

Effects of Medicinal Drugs on Fitness to Drive

“…For zopiclone 7.5 mg evening doses were found to produce residual driving impairment in the morning in several studies (Vermeeren et al 1998a(Vermeeren et al , 2002bLeufkens et al 2009b;Ramaekers et al, 2011). As expected, the residual effects after MOTN administration were even larger (Vermeeren et al 1998a).…”

“…For instance, esmirtazapine is metabolised through CYP2D6 and its clearance is twice as low in poor metabolisers as compared with extensive metabolisers. A recent study showed a more pronounced driving impairment in poor metabolisers after treatment with esmirtazapine (Ramaekers et al 2011). This suggests that subjects with genetic CYP deviations (e.g.…”

“…This suggests that subjects with genetic CYP deviations (e.g. poor CYP2D6 metabolisers) may be at higher risk when exposed to higher levels of drugs or metabolites that have the potential to impair car driving (Ramaekers et al 2011). …”

“…After single and repeated dosing with esmirtazapine 1.5 mg, driving performance was not impaired. A single dose of 4.5 mg did cause driving impairment (almost equivalent to BAC of 0.5 g/L) but after repeated doses this impairment was no longer present (Ramaekers et al 2011).…”

Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial

“…In the 2-week placebo-controlled study of 1.5, 3.0, and 4.5 mg of esmirtazapine in patients with chronic primary insomnia, changes in all measures of the residual effect were similar in the esmirtazapine and placebo groups [13]. In another study, which assessed the residual effects of esmirtazapine in healthy volunteers by evaluating actual driving performance, single doses of 4.5 mg were associated with residual daytime impairment, but this generally resolved after repeated administration [19]. Indeed, in an earlier randomized, double-blind, placebo-controlled, dose-finding study with esmirtazapine, there were reductions in daytime "energy" and "ability to work/function" with all doses (1.5, 3, and 4.5 mg) relative to placebo after the first but not the second night of treatment [20].…”