Comparative Bioavailability of Methylphenidate Powder for Prolonged-Release Oral Suspension and Methylphenidate Prolonged-Release Chewable Tablets versus Methylphenidate Immediate-Release Tablets: Phase 1, Single-Dose, Randomised, Crossover Studies in Healthy Adults

Various oral methylphenidate formulations are available to treat attention-deficit/hyperactivity disorder, but unmet needs still exist, particularly for individuals with swallowing difficulties or those requiring more flexible dosing options. Two phase 1 studies evaluated the comparative bioavailability and safety/tolerability of two prolonged-release (PR) methylphenidate formulations, an oral suspension and a chewable tablet, compared with an established immediate-release (IR) oral tablet formulation. Healthy volunteers were randomised to receive a single dose of methylphenidate PR oral suspension (total dose 60 mg; study 1) or chewable tablet (total dose 40 mg; study 2) and methylphenidate IR tablets (total dose 60 mg in study 1 and 40 mg in study 2) in a crossover manner, with a 7-day washout between treatment periods. Blood samples were collected over the 24-h post-administration period. Comparative bioavailability was defined as the 90% confidence interval (CI) of the relative mean plasma d-methylphenidate area under the plasma concentration–time curve from zero to last measurable concentration (AUClast) of methylphenidate PR formulation to methylphenidate IR being between 80 and 125%. Adverse events (AEs) were documented. In total, 24 individuals (mean age 39–42 years, approximately 50% male) were randomised in each study, of whom 23 received methylphenidate PR oral suspension in study 1 and 23 received methylphenidate PR chewable tablets in study 2; 24 received methylphenidate IR tablets in each study. The relative mean plasma d-methylphenidate AUClast ratios for methylphenidate PR formulation to methylphenidate IR tablets had 90% CIs of 82.30–87.18% in study 1 and 90.01–97.52% in study 2. Treatment-emergent AEs were reported in 26% and 22% of participants receiving the oral suspension and chewable tablets, respectively (versus 50% and 33% of those receiving the IR tablets in the respective studies). These AEs were typical of orally administered methylphenidate, mild in severity and, in general, resolved prior to study end. The methylphenidate PR oral suspension and chewable tablet formulations are bioequivalent in terms of the total extent of exposure (AUClast) to methylphenidate IR tablets and are tolerable in healthy adults. Methylphenidate is a drug often used to treat attention-deficit/hyperactivity disorder (ADHD). Various products (formulations) containing methylphenidate are available for doctors to prescribe, but it would be useful for additional formulations to be available to allow treatment to be more precisely tailored for each patient. In particular, formulations that release methylphenidate slowly into the bloodstream (‘prolonged-release’ [PR] formulations) are more effective at controlling symptoms over the course of each day than those that release methylphenidate more quickly (‘immediate-release’ [IR] formulations). Two studies were conducted to assess how two PR formulations of methylphenidate—a powder mixed with water (oral suspension) and a chewable tablet—compared with a commonly prescribed IR oral tablet formulation of methylphenidate in terms of the concentration of the drug achieved in the blood (termed ‘exposure’ to methylphenidate) and safety. In total, 24 healthy adults participated in each study. The studies were divided into two parts—initially, participants received either the PR formulation or the IR formulation; 7 days later, they received whichever formulation they had not received in the first part of the study. Over the 24 h, after each treatment was received, blood samples were taken to determine methylphenidate concentrations, and adverse effects were assessed. Exposure to methylphenidate was similar with each PR formulation versus the IR formulation. Further, the PR formulations were well-tolerated by participants, having adverse effects similar to those previously reported for methylphenidate. Therefore, the methylphenidate PR oral suspension and chewable tablet formulations can be considered important additions to the treatment options available for ADHD.

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