Pharmacokinetics of FT218, a Once-Nightly Sodium Oxybate Formulation in Healthy Adults

Abstract

Purpose: 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.

Methods: 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.

Results: In the pilot study, FT218 prototype 2 had a lower C_max, lower plasma concentration 8 h after dosing (C_8h), 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_max and slightly more than dose proportionality for AUC. The relative bioavailability study confirmed that FT218 6 g had lower C_max and C_8h than twice-nightly SO 6 g but equivalent AUC and comparable variability. In the food-effect study, FT218 6 g had longer t_max (1 h later), lower C_max (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.

Implications: Once-nightly FT218 at 4.5 and 6 g had lower overall C_max and C_8h and similar exposure and variability compared with twice-nightly SO. FT218 was generally well tolerated and comparable to twice-nightly SO.

Keywords: clinical study; narcolepsy; pharmacokinetic properties; sodium oxybate.