Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. II. Triazolam.

This study compares the time course of triazolam effects on psychomotor and cognitive skills with triazolam plasma concentrations in a combined pharmacokinetic-pharmacodynamic (sigmoid-Emax) model. Ten male subjects received a single oral dose (1 mg) of triazolam or placebo. The CNS impairment effects were measured by using computerized tracking, body sway, and digit symbol substitution tests, and triazolam plasma concentration was measured by gas chromatography. The drug-induced effect changes lagged behind the plasma drug level changes. The magnitude of the time lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma triazolam levels (t 1/2 keo). Essentially the same t 1/2 keo (approximately 6 min) was found for subcritical tracking, body sway, and digit symbol substitution tests. When using the predicted drug concentrations at the effect site, the hysteresis of the plasma concentration-effect disappears, suggesting that the hysteresis is not caused by drug induced tolerance. Moreover, the model allows for estimation of the effect site concentration that causes one-half of the maximal predicted effect (EC50, approximately 5 ng/ml) which is a measure of an individual's sensitivity to triazolam. On the basis of the EC50 values of the effect measures, body sway was slightly less sensitive to triazolam than subcritical tracking and digit symbol substitution tests.

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