Pharmocokinetics and pharmacodynamics of single-dose triazolam: electroencephalography compared with the Digit-Symbol Substitution Test.

Author(s): Greenblatt DJ, Gan L, Harmatz JS, Shader RI

Affiliation(s): Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, MA 02111, USA. dj.greenblatt@tufts.edu

Publication date & source: 2005-09, Br J Clin Pharmacol., 60(3):244-8.

Publication type: Comparative Study ; Randomized Controlled Trial; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.

AIMS: To investigate whether the electroencephalogram (EEG) directly reflects the CNS effects of benzodiazepines by evaluating the relation of the EEG to plasma drug concentrations and to Digit-Symbol Substitution Test (DSST) scores after a single dose of triazolam, a representative benzodiazepine agonist. METHODS: Thirteen healthy male subjects were given 0.375 mg triazolam or placebo in a double-blind crossover study. Plasma samples were collected during 8 h after dosage. Pharmacodynamic effects were measured by DSST and EEG at corresponding times. RESULTS: Pharmacokinetic parameters for triazolam were consistent with established values. Compared with placebo, triazolam significantly impaired psychomotor performance on the DSST (P < 0.001) and increased beta amplitude on the EEG (P < 0.002). DSST and EEG changes both closely tracked changes in plasma concentrations over time. The changes for the two measures were highly correlated with each other (r =-0.94, P < 0.001) based on aggregate values at individual time points. However, the variations in area under the curve of pharmacodynamic effect vs. time (AUCeffect) measured by either method did not reflect the variations in plasma AUC across individuals. The individual variability in AUCeffect from the EEG was similar to that measured by the DSST. CONCLUSIONS: Both the EEG and the DSST reflect the central benzodiazepine agonist effects of triazolam. Intrinsic variability in both measures is similar.