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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.
- Source :
-
Journal of child and adolescent psychopharmacology [J Child Adolesc Psychopharmacol] 2019 Apr; Vol. 29 (3), pp. 181-191. Date of Electronic Publication: 2019 Feb 27. - Publication Year :
- 2019
-
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).<br />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.<br />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.<br />Conclusions: Evening-dosed DR/ER-MPH demonstrated dose proportionality and can be administered with or without food. Significant accumulation is unlikely with multiple dosing.
- Subjects :
- Adult
Biological Availability
Cross-Over Studies
Diet
Female
Healthy Volunteers
Humans
Male
Middle Aged
Young Adult
Attention Deficit Disorder with Hyperactivity drug therapy
Central Nervous System Stimulants administration & dosage
Delayed-Action Preparations administration & dosage
Methylphenidate administration & dosage
Methylphenidate pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-8992
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of child and adolescent psychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30810347
- Full Text :
- https://doi.org/10.1089/cap.2018.0122