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Abstract Introduction KP1077 is under development as an oral medication for the treatment of rare sleep disorders with Excessive Daytime Sleepiness (EDS), including idiopathic hypersomnia (IH). The active ingredient in KP1077 is serdexmethylphenidate (SDX), a prodrug of d-methylphenidate (d-MPH). SDX is converted to d-MPH in the lower intestinal tract, with a delay and kinetics leading to a unique pharmacokinetic (PK) profile and an extended duration product. The objectives of the study were to assess the PK and safety after single morning and nighttime doses in healthy volunteers. Methods Heathy adult subjects received single oral doses of 240 mg SDX, either in the morning or at night, just before bedtime, in a randomized fashion with a washout of 6 days between treatments. Multiple blood PK samples and safety parameters were collected after each administration. Results A total of 15 subjects (9 males/6 females) were randomized with 14 completing both treatments. Both treatments were well-tolerated with adverse events typical for d-MPH. After the morning dose, d-MPH exposure was characterized by little or no d-MPH exposure for the first 4 hours followed by a gradual rise up to ~7 hour post-dose (Tmax), followed by a gradual decline. The rise in d-MPH concentrations after the nighttime dose was even more gradual than after the morning dose, with substantial levels reached around 10 hours postdose and a statistically significantly longer Tmax of 15 hours. Mean d-MPH peak concentrations were lower after the evening dose (22.0 ng/mL) compared to the morning dose (26.8 ng/mL) while total exposures (AUCinf) were similar (594 and 557 h*ng/mL, respectively). Conclusion Peak exposure of SDX-derived d-MPH and the bulk of the total d-MPH exposure after a nighttime dose of SDX occurs during the next morning compared to a morning dose where most exposure occurs the same day. This difference is likely due to a longer intestinal transit time and lower intestinal activity during the nighttime sleeping hours. This delay supports nighttime dosing of SDX in patients with IH who suffer from EDS and Sleep Inertia (difficulty waking up in the morning). Support (if any) Zevra Therapeutics
Braeckman et al. (Sat,) studied this question.