Age-related multiple-dose pharmacokinetics and anxiolytic effects of delorazepam (chlordesmethyldiazepam)

Abstract

The kinetics of delorazepam (chlordesmethyldiazepam; CDDZ), and its major metabolite, lorazepam (LRZ) during multiple-dose therapy have been evaluated in two groups of patients with primary or secondary anxiety. The 12 patients in group 1 were 46.8 +/- less than 13.2 years while the eight in group 2 were significantly older (69.7 +/- 7.8 years). All patients were given 0.5 mg twice daily of CDDZ for 30 days. Concentrations of CDDZ and LRZ in multiple blood samples collected during the study were determined by electron-capture gas-liquid chromatography. The degree of anxiety was evaluated from the Hamilton rating scale for anxiety (HRSA). CDDZ and LRZ accumulated in plasma but the rate of accumulation of CDDZ was slower than expected from studies in young volunteers and the half-life values were significantly related to age. Steady-state levels of glucuronated LRZ were also lower in elderly patients. Data indicate that CDDZ is more slowly eliminated and less metabolized as age increases. While pre-treatment scores of HRSA were similar in the two groups, older patients improved significantly less than those of group 1 and had also an higher incidence of side-effects. CDDZ levels positively correlated with improvement in group 1 but not in group 2.