EFFECTS OF AGE, GENDER, AND DIURNAL-VARIATION ON THE STEADY-STATE PHARMACOKINETICS OF BMS-181101, AN ANTIDEPRESSANT, IN HEALTHY-SUBJECTS

Objectives: To investigate the effects of age, gender, and diurnal var iation on the safety, tolerability, and steady-state pharmacokinetics of BMS-181101, and antidepressant, in humans. Methods: This was a mult iple-dose parallel-design study in 51 healthy subjects (12 young and 1 2 elderly men and 12 young and 15 elderly women). Each subject receive d a 15 mg oral dose of BMS-181101 ever 12 hours on days 1 through 6 an d 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 wa analyzed for BMS-181101 with use of an HPLC method. Results: Male subjects tolerated BMS-181101 better than femal e subjects. The mean values for area under the plasma concentration-ti me curve over the dosing interval tau (AUC(tau); 58.8 to 102.4 ng.hr/m l) and elimination half-life (tau(1/2); 5.7 to 10.4 hours) for the eld erly subjects were significantly greater than those for the young subj ects (39.0 to 64.3 ng.hr/ml and 3.2 to 4.5 hours). The mean values for peak plasma concentration (C-max; 14.7 to 25.2 ng/ml) and AUC(tau) (5 2.4 to 102.4 ng.hr/ml) for the women were significantly greater than t hose for the men (9.08 to 15.3 ng/ml and 39.0 to 73.6 ng.hr/ml). The m ean values for C-max (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 thos e after the evening dose on day 6 (9.08 to 17.3 ng/ml; 39.0 to 83.4 ng .hr/ml). Conclusions: An initial lower dose or appropriate titration o f daily doses of BMS-181101 may be necessary for the treatment of elde rly and female subjects, and the pharmacokinetics of BMS-181101 exhibi ted significant diurnal effects.