Dose‐Proportional and Stereospecific Pharmacokinetics of Methylphenidate Delivered Using an Osmotic, Controlled‐Release Oral Delivery System

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Abstract
Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose‐ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled‐release formulation (OROS®). Plasma concentrations of l‐methylphenidate were 40‐fold lower than those of d‐methylphenidate, whereas plasma concentrations of d‐α‐phenyl‐2‐piperidine acetic acid (d‐PPA) and l‐PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d‐methylphenidate were 42.2, 80.9, and 120 ng•h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l‐methylphenidate were only ∼1% of d‐methylphenidate (0.43, 0.96, and 1.82 ng•h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d‐ and l‐PPA were comparable. The dose‐normalized d‐ and l‐methylphenidate plasma concentration‐time profiles for the three treatment groups were superimposable. Similarly, dose‐normalized plasma concentrations of d‐ and l‐PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d‐methylphenidate AUCinf to d‐PPA AUCinf and as l‐methylphenidate AUCinf to l‐PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS® (methylphenidate HCl) exhibits dose‐proportional and linear pharmacokinetics.