PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF ZOPICLONE EFFECTS ON HUMAN CENTRAL-NERVOUS-SYSTEM

The present data shows the pharmacokinetics and concentration-effect r elationship of a single 7.5 mg oral dose of zopiclone in ten healthy v olunteers. Plasma concentrations and effects of zopiclone on central n ervous system as quantified by changes in saccadic peak velocity and d igit symbol substitution test were measured for 17 hr after ingestion of zopiclone. Pharmacokinetics was described with a linear one-compart ment open model. Maximum effects preceded peak plasma zopiclone concen trations causing a clockwise hysteresis, i.e. proteresis, in concentra tion versus effect loops. Therefore, pharmacodynamics was described bo th with a tolerance model and a model with distributional pseudo-toler ance where the concentration in the blood sampling site is assumed to equilibrate slower with arterial blood than the site of action of zopi clone. Both models related the changes in pharmacodynamics linearly to changes in zopiclone concentrations. The median (range) values for cl earance, volume of distribution and elimination half-life were 21 (15- 53) L/hr, 132 (58-161) L and 3.4 (1.7-5.7) hr,respectively. Both pharm acodynamic models were able to describe the relationship between zopic lone concentrations and changes in psychomotor performance equally wel l, However, because the pharmacodynamics of zopiclone were studied in a non-steady-state situation, the mechanism for proteresis, i.e. true tolerance versus distributional pseudotolerance cannot be identified.