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

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Abstract

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.

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Incledon, B., Incledon, C., Gomeni, R., Uchida, C. L., Morris, A., Perry, K., & Kapuscinski, J. (2022). Effect of Colonic Absorption on the Pharmacokinetic Properties of Delayed-Release and Extended-Release Methylphenidate: In Vivo, In Vitro, and Modeling Evaluations. Clinical Pharmacology in Drug Development, 11(8), 966–975. https://doi.org/10.1002/cpdd.1089

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