Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers

Abstract

Aims: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.

Methods: In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test.

Results: Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small.

Conclusions: Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Breath alcohol concentrations after intravenous alcohol infusion starting at t = −0.5 h and continuing until t = 5 h, in combination with oral administration (at t = 0 h) of GSK1144814 (open circles) or placebo (closed circles). Means are presented with SDs as error bars. , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 2

Alcohol infusion rates necessary to maintain a pseudo-steady-state alcohol serum concentration of 0.6 g l−1, starting at t = −0.5 h and continuing until t = 5 h, in combination with oral administration (at t = 0 h) of GSK1144814 (open circles) or placebo (closed circles). Means are presented with SDs as error bars. , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 3

Plasma concentrations of GSK1144814 after oral administration at t = 0 h, in combination with intravenous alcohol infusion starting at t = −0.5 h and continuing until t = 5 h. Means are presented with SDs as error bars

Figure 4

Adaptive tracking performance after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents measurements following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 5

Body sway after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents measurements following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 6

Saccadic peak velocity after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents measurements following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 7

Smooth pursuit measurements after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents measurements following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 8

Visual analogue scale (VAS) sedation scores after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents scores following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 9

Visual analogue scale (VAS) scores for the subjective effects of alcohol after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents scores following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo

Figure 10

Epworth sleepiness scale scores after intravenous alcohol infusion combined with oral administration (at t = 0 h) of either GSK1144814 (open circles) or placebo (closed circles). The grey curve represents scores following unblinded intravenous saline infusion (without drug administration) during a baseline study day preceding the first study period, which is included in the figure for reference. Means are presented with SDs as error bars. , unblinded saline infusion; , alcohol infusion + GSK1144814; , alcohol infusion + placebo