Effects of age, gender, and diurnal variation on the steady-state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects.

Abstract

To investigate the effects of age, gender, and diurnal variation on the safety, tolerability, and steady-state pharmacokinetics of BMS-181101, an antidepressant, in humans. This was a multiple-dose parallel-design study in 51 healthy subjects (12 young and 12 elderly men and 12 young and 15 elderly women). Each subject received a 15 mg oral dose of BMS-181101 every 12 hours on days 1 through 6 and one dose on day 7. After the evening dose on day 6 and morning dose on day 7, serial blood samples were collected at specified times after administration. Plasma was analyzed for BMS-181101 with use of an HPLC method. Male subjects tolerated BMS-181101 better than female subjects. The mean values for area under the plasma concentration-time curve over the dosing interval tau (AUC tau; 58.8 to 102.4 ng.hr/ml) and elimination half-life t1/2; 5.7 to 10.4 hours) for the elderly subjects were significantly greater than those for the young subjects (39.0 to 64.3 ng.hr/ml and 3.2 to 4.5 hours). The mean values for peak plasma concentration (Cmax; 14.7 to 25.2 ng/ml) and AUC tau (52.4 to 102.4 ng.hr/ml) for the women were significantly greater than those for the men (9.08 to 15.3 ng/ml and 39.0 to 73.6 ng.hr/ml). The mean values for Cmax (14.7 to 25.2 ng/ml) and AUC tau (54.8 to 102.4 ng.hr/ml) on the morning of day 7 were significantly greater than those after the evening dose on day 6 (9.08 to 17.3 ng/ml; 39.0 to 83.4 ng.hr/ml). An initial lower dose or appropriate titration of daily doses of BMS-181101 may be necessary for the treatment of elderly and female subjects, and the pharmacokinetics of BMS-181101 exhibited significant diurnal effects.