Model-Based Approach for Optimizing Study Design and Clinical Drug Performances of Extended-Release Formulations of Methylphenidate for the Treatment of ADHD

Clin Pharmacol Ther. 2017 Dec;102(6):951-960. doi: 10.1002/cpt.684. Epub 2017 Sep 19.


Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / blood
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Central Nervous System Stimulants / pharmacokinetics
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Delayed-Action Preparations / therapeutic use
  • Drug Compounding*
  • Drug Liberation
  • Humans
  • Methylphenidate / pharmacokinetics*
  • Methylphenidate / therapeutic use*
  • Models, Biological*
  • Research Design*
  • Therapeutic Equivalency
  • Treatment Outcome


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