Pharmacokinetic properties of once-daily oral low-dose mesylate salt of paroxetine (LDMP 7.5 mg) following single and multiple doses in healthy postmenopausal women.

Low-dose mesylate salt of paroxetine (LDMP 7.5 mg) is being investigated for the treatment of vasomotor symptoms associated with menopause. This Phase I, open-label, single- and multiple-dose study evaluated the pharmacokinetic properties, safety and tolerability of LDMP in postmenopausal, nonsmoking women aged ≥40 years. After a 3-week screening period, subjects received LDMP 7.5-mg capsules as a single dose on day 1 and then as multiple doses (once daily for 14 days) on Days 6-19. Blood samples were collected predose and up to 120 hours postdose on day 1 (single-dose pharmacokinetic profile), at predose (after 12 doses) on day 18, and at predose and up to 24 hours postdose on day 19 (multiple-dose pharmacokinetic profile). Capsules were taken with 240 mL of water while subjects were fasted. Safety was evaluated throughout the study. Twenty-four women (mean age, 56 years) completed the study. On day 1, median Tmax was ~6 hours, and mean t1/2 was 17.30 hours. Mean plasma concentrations attained predose on days 18 and 19 (days 13 and 14 of multiple dosing) and at 24 hours postdose (day 20) were similar, suggesting that steady state was achieved by day 13 of multiple dosing after 12 daily doses. Mean AUC0-24 h at steady state (day 14 of multiple dosing) was ~3-fold greater than AUC0-∞ on day 1, indicating nonlinear pharmacokinetics. Mean Cmax on day 14 of multiple dosing was ~5-fold greater than that attained on day 1, and the accumulation index (AUCday 19/AUCday 1) at steady state was 9.71. Fluctuation index (calculated as [(Cmax - Cmin)/Cavg ss] × 100) was 75.8%. Most subjects (23/24 [95.8%]) experienced at least 1 treatment-emergent adverse event (AE); however, most AEs (67 events in 22/24 subjects [91.7%]) were mild, and the remainder were moderate. Seventeen subjects experienced 33 AEs that were deemed possibly or probably related to LDMP. No serious AEs were reported, and no clinically meaningful changes in laboratory values, vital signs, or ECGs were observed. On multiple dosing, LDMP exhibited nonlinear pharmacokinetics and was well tolerated in these healthy postmenopausal women; the extent of accumulation was consistent with data from the published literature.