Pharmacokinetics and dose proportionality of FT218, an investigational controlled release formulation of sodium oxybate for once nightly dosing
Monteith D, Grassot J, Castellan C, and Roth T. Pharmacokinetics and dose proportionality of FT218, an investigational controlled release formulation of sodium oxybate for once nightly dosing. Sleep 2019; 42:A243.
Introduction: Sodium oxybate is indicated for the treatment of Excessive Daytime Sleepiness (EDS) and cataplexy in patients with narcolepsy. The currently marketed product, an immediate release (IR) sodium oxybate, is required to be taken twice nightly: at bedtime and 2.5 to 4 hours later, thus requiring patients to awaken in the middle of the night. FT218 is an investigational controlled-release (CR) formulation of sodium oxybate intended for once nightly dosing. The pharmacokinetics and dose proportionality of FT218 were evaluated in a Phase I study (PKFT218-1602). Methods: Subjects received 3 separate single-dose administrations of FT218 at bedtime, two hours post-evening meal, in a sequential order of 4.5g, 7.5g and 9g with a minimum 7-day washout between doses. Dose proportionality between the three doses was assessed using the power method. Results: For the 3 doses, mean pharmacokinetics exhibited similar overall profiles with median Tmax between 1.5 and 2 hours. Mean Cmax increased from 42.9 to 84.5 μg/mL across the increasing doses. Following Cmax, blood levels gradually decreased overnight. Mean concentrations at 8 hours were 4.8, 19.7 and 25.5 μg/mL for the 4.5, 7.5 and 9g doses respectively. The slope estimates were 1.02 (90% CI: 0.84-1.21) and 1.34 (90% CI: 1.17 -1.46) for Cmax and AUCinf respectively. Conclusion: FT218 achieved blood level profiles, when given at bedtime, consistent with a single CR dose. Dose proportionality was maintained for Cmax across the dosage range. Dose proportionality was exceeded with FT218 for AUCinf, but to a lesser extent than is known from public information for the IR sodium oxybate (2.3 fold increase for FT218 vs 3.8 for the IR). If approved, FT218 could offer an important new option for the treatment of EDS and cataplexy in narcolepsy with potentially improved compliance and quality of life benefits. FT218 is currently being evaluated for efficacy in narcolepsy patients in the Phase 3 REST-ON study.