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

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

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Pharmacometrica, La Fouillade, France.
Massachusetts General Hospital, Boston, Massachusetts, USA.
SUNY Upstate Medical University, Syracuse, New York, USA.
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.


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.

[Indexed for MEDLINE]

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