Berg Alexander K, Myrvik Michael J, Van Ess Peter J
Upsher-Smith Laboratories, Inc., Maple Grove, MN, United States.
Upsher-Smith Laboratories, Inc., Maple Grove, MN, United States.
Epilepsy Behav. 2017 Jun;71(Pt A):51-59. doi: 10.1016/j.yebeh.2017.02.023. Epub 2017 May 23.
Characterize pharmacokinetics, pharmacodynamics, and safety/tolerability of USL261 in geriatric adults to inform its potential for treating bouts of increased seizure activity.
Phase 1, randomized, double-blind, 2-way crossover study in healthy geriatric (≥65years; n=18) and non-geriatric (18-40years; n=12) adults evaluated single USL261 doses (2.5 and 5.0mg) administered intranasally. Pharmacokinetic parameters were estimated for midazolam and 1-hydroxymidazolam (active metabolite), including area under the plasma concentration-time curve (AUC), maximum plasma concentration (C), time to C (T), and half-life (t). Stanford Sleepiness Scale and Observer's Assessment of Alertness/Sedation assessed sedation; Digit-Symbol Substitution Test assessed psychomotor performance.
Midazolam exposure and plasma concentrations were higher in geriatric versus non-geriatric adults (geometric mean AUC [ng*h/mL] 2.5mg: 70 vs 54, respectively; 5.0mg: 157 vs 110; C [ng/mL] 2.5mg: 27.1 vs 22.5; 5.0mg: 55.8 vs 46.1). USL261 was rapidly absorbed, with no differences in median T (14.5-17.3min); mean t was longer in geriatric subjects. Similar age-related trends were observed for 1-hydroxymidazolam. Mean maximum observed pharmacodynamic effects were not significantly different between age groups, though were more pronounced following 5.0 versus 2.5mg (P<.05); return to baseline was generally achieved within 4h. USL261 was generally well tolerated, with similar adverse event rates between age groups.
Despite increased midazolam exposure in geriatric subjects, there were no differences between age groups in pharmacodynamic effects or adverse event rates. USL261 was rapidly absorbed and pharmacodynamic effects returned to baseline within ~4h, regardless of age. Dose-dependent pharmacokinetic and maximum pharmacodynamic effects were observed. Overall, pharmacokinetic findings for USL261 were similar to studies evaluating intravenous midazolam, whereas pharmacodynamic effects were less pronounced in the elderly than previously reported.
描述USL261在老年成人中的药代动力学、药效学及安全性/耐受性，以了解其治疗癫痫发作活动增加发作的潜力。
在健康老年（≥65岁；n=18）和非老年（18-40岁；n=12）成人中进行的1期随机、双盲、双向交叉研究，评估经鼻给予的单次USL261剂量（2.5和5.0mg）。估计咪达唑仑和1-羟基咪达唑仑（活性代谢物）的药代动力学参数，包括血浆浓度-时间曲线下面积（AUC）、最大血浆浓度（C）、达峰时间（T）和半衰期（t）。采用斯坦福嗜睡量表和观察者警觉性/镇静评估量表评估镇静情况；数字符号替换测试评估精神运动表现。
与非老年成人相比，老年成人中咪达唑仑的暴露量和血浆浓度更高（几何平均AUC[ng*h/mL]2.5mg：分别为70和54；5.0mg：157和110；C[ng/mL]2.5mg：27.1和22.5；5.0mg：55.8和46.1）。USL261吸收迅速，中位达峰时间（T）无差异（14.5-17.3分钟）；老年受试者的平均半衰期较长。1-羟基咪达唑仑也观察到类似的年龄相关趋势。各年龄组之间观察到的平均最大药效学效应无显著差异，但5.0mg比2.5mg时更明显（P<0.05）；一般在4小时内恢复到基线水平。USL261总体耐受性良好，各年龄组不良事件发生率相似。
尽管老年受试者中咪达唑仑暴露量增加，但各年龄组在药效学效应或不良事件发生率方面无差异。无论年龄如何，USL261吸收迅速，药效学效应在约4小时内恢复到基线水平。观察到剂量依赖性药代动力学和最大药效学效应。总体而言，USL261的药代动力学结果与评估静脉注射咪达唑仑的研究相似，而老年患者的药效学效应比先前报道的要轻。
