Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults

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.

An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations

“…Similar to other ER MPH formulations, the pharmacokinetic profiles of healthy adults and children and adolescents with ADHD are nearly superimposable after adjusting for dose and body weight [73,75]. In five separate single-dose pharmacokinetic studies of DR/ER-MPH, early drug exposure from 0 to 10 hours after evening dosing was <5% of total drug exposure in healthy adults and in adolescents and children with ADHD, confirming that there is no drug release while the patient sleeps [73][74][75]. After the delay in initial drug release, plasma MPH concentrations increased rapidly and peaked at 14 to 16 hours postdose in healthy adults and 16 to 18 hours postdose in children and adolescents with ADHD.…”

“…The outer DR layer comprises hydrophobic, hygroscopic, and pH-dependent polymers designed to provide a prolonged, predictable delay in the timing of initial MPH release, which is intended to offer a therapeutic effect upon awakening. The inner ER layer, composed of hydrophobic and soluble polymers, is designed to provide a controlled, extended release of MPH with the goal of maintaining efficacy throughout the rest of the day [73][74][75].…”

“…Evening-dosed DR/ER-MPH exhibits a single-peak pharmacokinetic profile with a consistent, predictable delay in the initial release of MPH until the early morning (i.e.~8-10 hours after ingestion), followed by a period of extended, controlled release across the day [73][74][75]. Similar to other ER MPH formulations, the pharmacokinetic profiles of healthy adults and children and adolescents with ADHD are nearly superimposable after adjusting for dose and body weight [73,75].…”

“…This was followed by a slower decline in drug concentrations, with more than 50% of drug exposure occurring after peak concentrations were reached, suggesting that DR/ER-MPH has a prolonged absorption phase and thereby protracted elimination phase [73]. The apparent t 1/2 of DR/ER-MPH administered to healthy adults under fasted conditions is approximately 5.9 to 6.5 hours [73][74][75].…”

“…DR/ER-MPH is available in five dosage strengths of 20, 40, 60, 80, and 100 mg, and has demonstrated dose proportionality between the 20 and 100 mg doses [74,75]. Multiple-dose pharmacokinetics of DR/ER-MPH were simulated at doses of 20 and 100 mg and it was determined that there was no significant accumulation of MPH compared with single doses, and that steady state is reached by the second dose [74]. The relative bioavailability of once-daily DR/ER-MPH compared with a similar dose of thrice-daily IR MPH in healthy adults was 73.9% [74,75].…”