The pharmacokinetics of once-nightly controlled- release Sodium Oxybate (FT218): overview of results from four phase 1 studies
Thorpy M, Dubow J, Monteith D, Grassot J, Roth T, Winkelman J, and Corser B. The pharmacokinetics of once-nightly controlled- release Sodium Oxybate (FT218): overview of results from four phase 1 studies. Sleep Med 2019; 64:S385.
Introduction: Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The approved effective doses of sodium oxybate are 6, 7.5 and 9 g per night, divided in two doses - the first taken at bedtime and the second 2.5 - 4 hours later. FT218 is an investigational controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel's proprietary Micropump™ technology. Here we present pharmacokinetic data for FT218. Materials and methods: Four crossover, single-dose pharmacokinetic studies were conducted in healthy volunteers. The first was a pilot pharmacokinetic study (n=16) comparing three formulations of FT218 4.5 g compared to twice-nightly sodium oxybate immediate release (IR) 4.5 g (in two divided doses of 2.25 g). The second was a dose-proportionality study (n=20) evaluating FT218 4.5, 7.5 and 9 g (n=20). The third, a relative bioavailability study (n=28) was completed comparing FT218 6 g to twice-nightly sodium oxybate IR 6 g (in two divided doses of 3 g). The fourth was a food effect study (n=16) of FT218 at 6g. Results: The pilot pharmacokinetic study demonstrated that one prototype of FT218 (prototype 2) exhibited a lower overall Cmax, and a comparable C8h and similar AUC to twice-nightly sodium oxybate IR at the 4.5 g total dose. Inter-subject variability of FT218 and twice-nightly sodium oxybate IR was comparable. Exploratory pharmacodynamic data, with no statistical analysis, showed similar sleep quality and morning alertness following dosing between FT218 and twice-nightly sodium oxybate IR. This prototype was selected for further development to be used in the current Phase 3 REST-ON pivotal safety and efficacy study. The dose proportionality study demonstrated that FT218 was dose proportional for Cmax and AUC was slightly more than dose proportional. The relative bioavailability study comparing FT218 6 g to twice-nightly sodium oxybate IR 6 g (in two divided doses of 3 g) confirmed that FT218 had a lower overall Cmax than twice-nightly sodium oxybate IR, while AUC was equivalent. C8h level and variability was comparable between FT218 and twice-nightly sodium oxybate IR. A food effect study of FT218 at 6 g, demonstrated that in the fed, compared to the fasted state, FT218 had a longer Tmax, lower Cmax and decreased AUC (Tmax 1-hour slower, Cmax 67%, AUC 86% of fasted values). For all studies, Adverse Events (AEs) with FT218 were mostly mild or moderate in severity, non-serious and known AEs associated with sodium oxybate. The safety profiles of FT218 and twice-nightly sodium oxybate IR at 4.5 and 6 g appeared similar. The most common adverse events were known AEs for sodium oxybate including somnolence, dizziness and nausea. Conclusions: Once-nightly FT218 at 4.5 and 6 g demonstrated a lower overall Cmax and similar exposure to twice-nightly sodium oxybate IR, with similar C8h plasma levels and C8h variability. FT218 was generally safe and well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate IR. The efficacy and safety of FT218 in narcolepsy is currently being evaluated in the pivotal, randomized, double-blind, placebo-controlled Phase 3 REST-ON study.