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

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.

A convolution‐based in vitro‐in vivo correlation model for methylphenidate hydrochloride delayed‐release and extended‐release capsule

“…Study 2: In vitro dissolution study of fast, medium, and slow-release formulations of DR/ER-methylphenidate hydrochloride Study 2 was an in vitro study of three different release formulations of DR/ER-methylphenidate hydrochloride. 10 The dissolution testing for the first 2 h took place in 0.1 N hydrochloride, and then for the next 4 h in pH 6.0 phosphate buffer, and finally in pH 7.2 phosphate buffer for the remaining time (6-24 h).…”

“…Study 3: In vivo PK study of fast, medium, and slow-release formulations of DR/ER-methylphenidate hydrochloride Study 3 was a phase I, single-center, single-dose, openlabel, randomized, crossover, comparative bioavailability study of three formulations of DR/ER-methylphenidate hydrochloride in healthy adults. 10 A total of 18 subjects were randomly assigned to six treatment sequence cohorts of three subjects each in a crossover fashion (as described in Table S1) to receive the three different formulations of DR/ER-methylphenidate hydrochloride 100 mg described in study 2: fast, medium (DR/ER-methylphenidate hydrochloride formulation and reference treatment), and slow. All subjects were dosed under fasted conditions.…”