Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers

This study describes for the first time the pharmacokinetic and pharmacodyn amic modeling of the psychomotor and amnesic effects of a single 2-mg oral dose of lorazepam in healthy volunteers. Twelve healthy volunteers were inc luded in this randomized, double-blinded, placebo-controlled two-way crosso ver study. The effect of lorazepam was examined for a battery of tests that explored mood, vigilance, psychomotor performance, and memory. The pharmac okinetic and pharmacodynamic modeling of these tests was performed using th e indirect response model. Vigilance and psychomotor performance were signi ficantly impaired. Short-term memory was not affected, but a paradoxical te ndency to improvement of the score was observed 0.4 hours after drug intake . Significant impairment was observed for immediate and delayed cued verbal recall, for immediate and delayed free recall, and for picture recognition as well as for visual-verbal recall, but not for cued visual-spatial recal l or priming. Globally, the different effects were greatest between 0.4 to 3 hours after dosing. However, the time course profile of the recovery peri od suggests a possible dissociation between the kinetics of the effects of lorazepam on vigilance, psychomotor performance, and visual episodic memory , on the one hand, and on verbal episodic memory, on the other. The pharmac okinetic and pharmacodynamic model used two compartments with first-order a bsorption to describe the lorazepam concentrations and an indirect response model with inhibition or stimulation of Kin to describe the effects. The m ean values for calculated median effective concentration (EC50) derived fro m the pharmacokinetic and pharmacodynamic modeling of the different tests r anged from 11.3 to 39.8 ng/mL. According to these EC,, values, lorazepam se emed to be more potent on the delayed-recall trials than on the immediate-r ecall trials; similar observations were made concerning the free-recall ver sus cued-recall trials. The previously stated results suggest that the test s performed in this study represent sensitive measurements of the effects o f lorazepam on the central nervous system. Moreover, the parameter values d erived from pharmacokinetic and pharmacodynamic modeling, especially, the E C50 values, may provide sensitive indices that can be used to compare the c entral nervous system effects of benzobiazepines.