Effect of Colonic Absorption on the Pharmacokinetic Properties of Delayed-Release and Extended-Release Methylphenidate: In Vivo, In Vitro, and Modeling Evaluations

Clin Pharmacol Drug Dev. 2022 Aug;11(8):966-975. doi: 10.1002/cpdd.1089. Epub 2022 Mar 22.


Most stimulants used to treat attention-deficit/hyperactivity disorder are administered in the morning and absorbed in the upper gastrointestinal tract. DR/ER-MPH (formerly HLD200), an evening-dosed delayed-release and extended-release methylphenidate, is predicted to be absorbed in the proximal colon. The pharmacokinetic (PK) profile of DR/ER-MPH is characterized by an 8- to 10-hour delay in initial methylphenidate absorption and a subsequent gradual increase in plasma concentration, followed by a slow decline. To examine the relationship of absorption site to pharmacokinetics, the DR/ER-MPH formulation was altered to release methylphenidate in the small intestine and distal colon. The 3 formulations were administered in an open-label, 3-way, crossover study in healthy adults (N = 18). Compared with the small intestine formulation, the PK profile of the proximal colon (DR/ER-MPH) formulation exhibited a longer delay before initial methylphenidate absorption, decreased peak methylphenidate concentration, increased time to peak concentration, and decreased bioavailability; these characteristics were amplified in the distal colon formulation. Safety profiles fell within the expectations for methylphenidate products. Modeled PK profiles were similar between the small intestine formulation and a morning-dosed extended-release methylphenidate (both predicted to release methylphenidate in the upper gastrointestinal tract), providing additional evidence that the PK profile of DR/ER-MPH is shaped by colonic absorption.

Keywords: attention-deficit/hyperactivity disorder; colonic absorption; drug delivery; methylphenidate; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Central Nervous System Stimulants* / pharmacokinetics
  • Colon
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Humans
  • Methylphenidate* / pharmacokinetics


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