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

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.