Abstract
Objectives: HLD200, an oral, once-daily, evening-dosed, delayed-release, and extended-release methylphenidate (DR/ER-MPH), was designed to provide efficacy from the early morning, throughout the day, and into the evening to individuals with attention-deficit/hyperactivity disorder. The objectives were to evaluate DR/ER-MPH pharmacokinetic (PK) properties in healthy adults, including dose proportionality, food effect, the potential of accumulation using multiple-dose modeling, and bioavailability compared to an immediate-release MPH (IR MPH).Methods: Three open-label, single-dose, crossover studies were conducted, all with a 7-day washout between treatments. In Study I, 20 subjects received evening-dosed DR/ER-MPH (20 and 100 mg) followed by a medium-fat breakfast; 13 subjects received a subsequent 100-mg dose of DR/ER-MPH followed by a low-fat breakfast. In Study II, 18 subjects were evaluated after receiving evening-dosed DR/ER-MPH (100 mg) under 3 conditions: immediately after a high-fat meal, sprinkled on applesauce, and in a fasted state. In Study III, 11 and 12 subjects received evening-dosed DR/ER-MPH (100 mg) and morning-dosed IR MPH (20 mg), respectively.Results: DR/ER-MPH demonstrated dose proportionality between 20- and 100-mg doses. DR/ER-MPH PK parameters were not significantly affected by breakfast content or by sprinkling capsule contents. A high-fat meal immediately preceding evening dosing did not affect total MPH exposure but lowered peak MPH exposure by 14% and 11% versus fasted and sprinkled states, and time to peak exposure was delayed by ∼2.5 hours; these PK differences are unlikely to be clinically significant. Based on multiple-dose simulations using data from Study I, negligible accumulation of DR/ER-MPH was predicted. The relative bioavailability for DR/ER-MPH compared to IR MPH was 73.9%. No serious adverse events (AEs) were reported, and the observed AEs were consistent with MPH. There were no discontinuations in Studies I and III, but three participants withdrew in Study II due to AEs.Conclusions: Evening-dosed DR/ER-MPH demonstrated dose proportionality and can be administered with or without food. Significant accumulation is unlikely with multiple dosing.
Highlights
Long-acting stimulants are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD), with methylphenidate (MPH) frequently prescribed to children and adolescents with ADHD (Pliszka et al 2007; Wolraich et al 2011)
Due to its delivery to the relatively less absorptive colon, DR/ER-MPH displayed an extended elimination phase throughout the following day and decreased DN bioavailability compared to immediate-release MPH (IR MPH)
Evening-dosed DR/ER-MPH represents a shift in the approach to the timing of MPH delivery to address the unmet need for a oncedaily ADHD medication that provides efficacy upon awakening and into the evening (Pliszka et al 2017)
Summary
Long-acting stimulants are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD), with methylphenidate (MPH) frequently prescribed to children and adolescents with ADHD (Pliszka et al 2007; Wolraich et al 2011). Clinically meaningful control of ADHDassociated early morning functional impairment and symptoms from the time of awakening until arrival at school, but not at the expense of efficacy later in the day, remains a significant unmet need in stimulant-treated youth with ADHD (Sallee 2015; Faraone et al 2017). Some MPH formulations have a delay in the initial onset of action of up to 2 hours (Childress 2016), which can result in inadequate symptom control and impaired functioning during the before-school early morning routine, a challenging time of day for school-aged children with ADHD and their families (Whalen et al 2006; Sallee 2015; Faraone et al 2017)
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