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 Cmax, lower plasma concentration 8 h after dosing (C8h), 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 Cmax and slightly more than dose proportionality for AUC. The relative bioavailability study confirmed that FT218 6 g had lower Cmax and C8h than twice-nightly SO 6 g but equivalent AUC and comparable variability. In the food-effect study, FT218 6 g had longer tmax (1 h later), lower Cmax (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 Cmax and C8h and similar exposure and variability compared with twice-nightly SO. FT218 was generally well tolerated and comparable to twice-nightly SO.