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

Abstract

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.

Figure 1

(a) Plasma concentrations of triazolam at corresponding times (mean ± SE, n = 13). Line represents the function of best fit based on a linear sum of two exponential terms, modified by a lag time (0.16 h) elapsing prior to the start of absorption; (b) Pharmacodynamic effects of triazolam and placebo at corresponding times (mean ± SE, n = 13) for the DSST; (c) Pharmacodynamic effects of triazolam and placebo at corresponding times (mean ± SE, n = 13) for the EEG

Figure 2

(a) Correlation between DSST and EEG measures using mean values of EEG change and DSST change at corresponding times (r = −0.94, P < 0.001) based on an exponential equation ( y = −1.13x^1.4+ 3.78). Relative asymptotic standard errors (in per cent) for parameter estimates in the fitted function were: 1.13 (±103%); 1.4(±29%); 3.78 (±95%); (b) The relation of mean plasma triazolam concentrations to mean DSST changes over baseline (placebo-normalized) at the corresponding time (r = −0.99). Solid line represents an exponential equation [E = −2.14C^2.93 + 0.33] fitted to data points using nonlinear regression. Relative asymptotic standard errors (in percent) for parameter estimates in the fitted function were: 2.14 (±33%); 2.93 (13%); 0.33 (±288%); (c) Relation between the plasma triazolam AUC and the placebo-normalized AUC_effect for DSST change score among 13 subjects (r = 0.04, NS). Units for AUC_effect (y-axis) are: DSST change score × h. Units for plasma AUC (x-axis) are: ng ml⁻¹ × h