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.

Keywords: attention-deficit/hyperactivity disorder; dose proportionality; food effect; methylphenidate; pharmacokinetics; relative bioavailability.

FIG. 1.

Mean methylphenidate plasma concentrations after single evening doses of 20- and 100-mg DR/ER-MPH followed by a medium-fat breakfast (n = 20) in Study I (Part 1). Error bars represent + standard deviation of the mean. DR/ER-MPH, delayed-release and extended-release methylphenidate.

FIG. 2.

(A) Mean methylphenidate plasma concentrations after single evening doses of 100-mg DR/ER-MPH followed by low- and medium-fat breakfasts (n = 13) in Study I (Part 2); (B) mean methylphenidate plasma concentration after single evening doses of 100-mg DR/ER-MPH in fed, sprinkled, and fasted states followed by a high-fat breakfast (n = 18) in Study II. Error bars represent + standard deviation of the mean. DR/ER-MPH, delayed-release and extended-release methylphenidate.

FIG. 3.

Mean methylphenidate plasma concentrations after single evening doses of 100-mg DR/ER-MPH (n = 11) and 20-mg IR MPH (n = 12) in Study III. Error bars represent + standard deviation of the mean. DR/ER-MPH, delayed-release and extended-release methylphenidate; IR MPH, immediate-release methylphenidate.

FIG. 4.

Concentration–time profile of the observed single-dose PK profile and the simulated multiple-dose PK profile of DR/ER-MPH (A) 20 mg and (B) 100 mg. Red circles show observed single-dose PK profile of DR/ER-MPH from Study I; blue lines show the simulated multiple-dose PK profile. PK, pharmacokinetic; DR/ER-MPH, delayed-release and extended-release methylphenidate.