PHARMACOKINETICS AND PHARMACODYNAMICS OF TRIAZOLAM AFTER 2 INTERMITTENT DOSES IN OBESE AND NORMAL-WEIGHT MEN

This study was designed to determine whether differences in alpha-1 ac id glycoprotein and free drug concentrations result in an altered resp onse to triazolam. Twelve normal-weight and 12 obese adult male subjec ts received intravenous doses of triazolam, 0.5 mg, on two occasions s eparated by 1 week. There was a small difference in the alpha-1 acid g lycoprotein concentrations between groups but no difference in free fr action of triazolam. There was a longer terminal half-life (t 1/2 beta ) in the obese subjects (3.16+/-0.87 vs. 3.83 +/- 1.24, p = 0.0098). O verall, week 1 data revealed no difference in effect between normal an d obese subjects. However, response data reveal a pattern of increased sensitivity with the second exposure to triazolam. For example, area under the effect curve (AUEC) on all tests was significantly greater i n week 2 for both groups of subjects. For a memory test and sedation f rom 0 to 12 hours, AUEC/free AUC ratios were significantly greater in week 2 for all subjects. The obese had a higher ratio on week 2 than o n week 1 for all psychomotor tests and sedation (0 to 4.5 hours; p < 0 .05). The results of modeling psychomotor impairment-concentration dat a pooled by group for each week continue the pattern: week 1 data are similar between the obese and normal-weight subjects. Although EC(50) values are up to 15% lower in week 2 for the normal-weight subjects, E C(50) values are as much as 66% lower in week 2 for the obese, where a lower EC(50) indicates greater sensitivity. Logistic regression of th e recognition data is consistent with these results. Thus, the AUEC, A UEC/f AUC, EC(50), and logistic regression results concur, suggesting similarity in response between normal-weight and obese subjects after the first exposure to triazolam and a greater response after the secon d exposure, particularly in the obese.