Avadel Pharmaceuticals, Chesterfield, MO, USA.
Avadel Pharmaceuticals, Chesterfield, MO, USA.
Clin Ther. 2021 Apr;43(4):672.e1-672.e14. doi: 10.1016/j.clinthera.2021.01.017. Epub 2021 Feb 23.
FT218 is an investigational, once-nightly, modified-release formulation of sodium oxybate (SO). SO effectively treats excessive daytime sleepiness and cataplexy in patients with narcolepsy. Current approved SO formulations, at effective doses of 6, 7.5, and 9 g, require twice-nightly divided dosing, with the first dose taken at bedtime and the second 2.5-4 h later. The purpose of the following studies was to evaluate the pharmacokinetic properties, safety profile, and tolerability of FT218 in healthy adults.
Four crossover, single-dose studies were conducted. The first was a pilot study (n = 16) that compared 3 prototype formulations of FT218 4.5 g to twice-nightly SO 4.5 g (2 divided doses of 2.25 g); the second, a dose-proportionality study (n = 20) that evaluated FT218 4.5, 7.5, and 9 g; the third, a relative bioavailability study (n = 28) that compared FT218 6 g with twice-nightly SO 6 g (2 divided doses of 3 g); and the fourth, a food-effect study (n = 16) of FT218 6 g.
In the pilot study, FT218 prototype 2 had a lower C, lower plasma concentration 8 h after dosing (C), similar exposure (AUC), and comparable interperson variability to twice-nightly SO 4.5 g. Exploratory pharmacodynamic data indicated similar sleep quality and morning alertness between FT218 and twice-nightly SO. Prototype 2 was selected for further development. In the dose-proportionality study, FT218 had dose proportionality for C and slightly more than dose proportionality for AUC. The relative bioavailability study confirmed that FT218 6 g had lower C and C than twice-nightly SO 6 g but equivalent AUC and comparable variability. In the food-effect study, FT218 6 g had longer t (1 h later), lower C (67%), and decreased AUC (86%) in fed versus fasted states. For all studies, adverse events with FT218 were mostly mild or moderate in severity, nonserious, and known to be associated with SO. Most common adverse events included somnolence, dizziness, and nausea. Safety profiles of FT218 and twice-nightly SO at 4.5 and 6 g were similar.
Once-nightly FT218 at 4.5 and 6 g had lower overall C and C and similar exposure and variability compared with twice-nightly SO. FT218 was generally well tolerated and comparable to twice-nightly SO.
FT218 是一种研究性的、每晚一次的钠双氧西泮（SO）改良释放制剂。SO 可有效治疗嗜睡症患者的日间过度嗜睡和猝倒。目前批准的 SO 制剂，在有效剂量为 6、7.5 和 9g 时，需要每晚两次分剂量给药，第一次在睡前给药，第二次在 2.5-4 小时后给药。以下研究的目的是评估 FT218 在健康成年人中的药代动力学特性、安全性和耐受性。
进行了四项交叉、单次剂量研究。第一项是一项初步研究（n=16），比较了 FT218 的三种原型制剂 4.5g 与每晚两次 SO 4.5g（2 次 2.25g 剂量）；第二项是剂量比例研究（n=20），评估了 FT218 4.5、7.5 和 9g；第三项是相对生物利用度研究（n=28），比较了 FT218 6g 与每晚两次 SO 6g（2 次 3g 剂量）；第四项是 FT218 6g 的饮食影响研究（n=16）。
在初步研究中，FT218 原型 2 的 C 较低，给药后 8 小时的血浆浓度 C 较低，暴露量（AUC）相似，个体间变异性与每晚两次 SO 4.5g 相似。探索性药效学数据表明，FT218 和每晚两次 SO 之间的睡眠质量和早晨警觉性相似。原型 2 被选为进一步开发。在剂量比例研究中，FT218 的 C 和 AUC 均具有剂量比例性，AUC 略高于剂量比例性。相对生物利用度研究证实，FT218 6g 的 C 和 C 低于每晚两次 SO 6g，但 AUC 相当，变异性可比较。在饮食影响研究中，FT218 6g 在进食状态下的 t（1 小时后）较长，C（67%）和 AUC（86%）较低。对于所有研究，FT218 的不良事件大多为轻度或中度，非严重，与 SO 相关。最常见的不良事件包括嗜睡、头晕和恶心。FT218 每晚 4.5 和 6g 与每晚两次 SO 4.5 和 6g 的安全性相似。
每晚一次的 FT218 4.5 和 6g 的总体 C 和 C 较低，与每晚两次 SO 相比，暴露量和变异性相似。FT218 通常耐受性良好，与每晚两次 SO 相当。
