Development of a New Once-a-Day Formulation of Methylphenidate for the Treatment of Attention-deficit/Hyperactivity Disorder: Proof-of-Concept and Proof-of-Product Studies
Abstract
Background The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. Methods Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. Results The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7…
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Efficacy of long-acting stimulants in the laboratory school setting has been demonstrated for children with ADHD across the day and at 12 and 13 hours postdose.
“While similar studies in adults are limited, efficacy of long-acting stimulants in the laboratory school setting has been demonstrated for children with ADHD across the day and at 12 [15,22,25,33,34] and 13 hours postdose [16].”
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- Authors
- Swanson, J., Gupta, S., Lam, A., Shoulson, I., Lerner, M., Modi, N., Lindemulder, E., & Wigal, S.
- Affiliations
- University of California, Irvine (US)
- University of Rochester Medicine (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2003-02-01
- Volume
- 60
- Issue
- 2
- Pages
- 204
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W1986046877
- Cited by
- 248
- References
- 6
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 8 · 2013: 11 · 2012: 8
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- methylphenidate, attention deficit hyperactivity disorder, OROS methylphenidate, osmotic pump, sustained-release formulation, acute tolerance, tachyphylaxis, pharmacokinetics, pharmacodynamics, children
- MeSH terms
- Administration, Oral, Adolescent, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Capsules, Child, Clinical Protocols, Delayed-Action Preparations, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Humans, Intestinal Absorption, Methylphenidate, Placebos, Tachyphylaxis, Cohort Studies, Drug Delivery Systems, Treatment Outcome, Cross-Over Studies
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