Noven Pharmaceuticals, Inc, New York, New York 10118, USA.
Clin Ther. 2013 Jun;35(6):862-9. doi: 10.1016/j.clinthera.2013.05.001.
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.
低剂量帕罗西汀甲磺酸盐（LDMP 7.5 毫克）正在被研究用于治疗与绝经相关的血管舒缩症状。
这项 I 期、开放标签、单次和多次剂量研究评估了 LDMP 在绝经后、不吸烟的年龄≥40 岁女性中的药代动力学特性、安全性和耐受性。
在 3 周的筛选期后，受试者在第 1 天接受 LDMP 7.5 毫克胶囊单次剂量，然后在第 6-19 天接受多次剂量（每日一次，共 14 天）。在第 1 天（单次剂量药代动力学特征）、第 18 天（单次剂量后第 12 次给药前）和第 19 天（多次剂量后第 1 次给药前）采集血样，直至给药后 120 小时。胶囊在禁食时与 240 毫升水一起服用。整个研究过程中评估安全性。
24 名女性（平均年龄 56 岁）完成了这项研究。第 1 天，中位 Tmax 约为 6 小时，平均 t1/2 为 17.30 小时。第 18 天和第 19 天（多次剂量第 13 天和第 14 天）及第 24 小时（多次剂量第 20 天）的预给药时平均血浆浓度相似，表明在多次剂量第 12 天每日给药后第 13 天达到稳态。稳态时的平均 AUC0-24 h（多次剂量第 14 天）是第 1 天 AUC0-∞的约 3 倍，表明存在非线性药代动力学。多次剂量第 14 天的平均 Cmax 是第 1 天的约 5 倍，稳态时的蓄积指数（AUCday 19/AUCday 1）为 9.71。波动指数（计算方法为[（Cmax - Cmin）/Cavg ss] × 100）为 75.8%。大多数受试者（24 名中的 23 名[95.8%]）发生了至少 1 次治疗后出现的不良事件（AE）；然而，大多数 AE（22 名受试者中的 67 项[91.7%]）为轻度，其余为中度。17 名受试者发生了 33 次被认为可能或肯定与 LDMP 有关的不良事件。未报告严重不良事件，实验室值、生命体征或心电图也未观察到有临床意义的变化。
在多次剂量给药时，LDMP 在这些健康的绝经后女性中表现出非线性药代动力学特征且具有良好的耐受性；蓄积程度与已发表文献中的数据一致。
