Pharmacokinetic-pharmacodynamic modeling of midazolam effects on the human central nervous system

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Abstract
The effect of midazolam on α‐activity of the EEG and latency of the P‐100 of the visual evoked response (VER) was studied in six healthy subjects. Drug concentration was related to effect with the Emax model that was used with either a threshold drug concentration or a sigmoid exponent. An effect compartment was included in the pharmacokinetic‐pharmacodynamic model. Four subjects showed hysteresis, and mean values of half‐lives‐keo ranged from 0.26 to 0.60 hour. Mean values of EC50 ranged from 42.0 to 48.1 ng/ml. Goodness of fit did not differ significantly between the sigmoid Emax model and the threshold Emax model. The sigmoid exponent estimated was 3.7 ± 1.8 (EEG, mean ± SD) and 2.9 ± 1.4 (VER); the threshold concentration was estimated at 15.7 ± 11.1 ng/ml (EEG) and 11.3 ± 7.0 ng/ml (VER). We conclude that the Emax model adequately describes the relationship between midazolam concentration and effect and that the sigmoid exponent can be substituted by a threshold drug concentration, with a comparable fit of the model to the data. Clinical Pharmacology and Therapeutics (1988) 44, 14–22; doi:10.1038/clpt.1988.106