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

J Child Adolesc Psychopharmacol. 2019 Apr;29(3):181-191. doi: 10.1089/cap.2018.0122. Epub 2019 Feb 27.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Biological Availability
  • Central Nervous System Stimulants / administration & dosage*
  • Cross-Over Studies
  • Delayed-Action Preparations / administration & dosage*
  • Diet
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Methylphenidate* / administration & dosage
  • Methylphenidate* / pharmacokinetics
  • Middle Aged
  • Young Adult


  • Central Nervous System Stimulants
  • Delayed-Action Preparations
  • Methylphenidate