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

Arch Gen Psychiatry. 2003 Feb;60(2):204-11. doi: 10.1001/archpsyc.60.2.204.


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 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy.

Conclusions: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Capsules / administration & dosage
  • Capsules / pharmacokinetics
  • Capsules / therapeutic use
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / pharmacokinetics
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Clinical Protocols
  • Cohort Studies
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Delivery Systems
  • Humans
  • Intestinal Absorption
  • Methylphenidate / administration & dosage*
  • Methylphenidate / pharmacokinetics
  • Methylphenidate / therapeutic use
  • Placebos
  • Tachyphylaxis / physiology
  • Treatment Outcome


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