A Single‐Dose, Two‐Way Crossover, Bioequivalence Study of Dexmethylphenidate HCl with and without Food in Healthy Subjects

Abstract

Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(C(max)) and ln[(AUC(0-infinity))], respectively. There was a marginal but statistically significant 1-hour increase in t(max) in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased ( approximately 14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean t(max) for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.

Differential Pharmacokinetics and Pharmacodynamics of Methylphenidate Enantiomers

“…This finding is consistent with that of extensive enantiospecific pharmacokinetic studies that have measured both isomers and found the l-isomer to generally attain only a small fraction of that of circulating concentrations of d-MPH (Table 1). [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] In addition, the plasma half-life (t 1/2 ) of d-MPH is markedly longer than that of l-MPH. 22 The presystemic metabolism and clearance of d,l-MPH is an enantioselective process resulting in markedly higher plasma concentrations of d-MPH relative to l-MPH.…”

Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate

“…Second, the study by Quinn et al (2004) dosed the subjects with breakfast; the study by Patrick et al (2013) provided a light breakfast 1 hour before dosing. Food has been reported to delay the d-MPH time to maximum plasma concentration and may increase total MPH exposure (Midha et al, 2001;Teo et al, 2004). Third, the earlier study by Quinn et al (2004) used children with ADHD (n = 32).…”

Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates

“…Panel A: Data represent model simulated (lines) and observed individual (circles) plasma concentrations of d -MPH after oral dosing with 20 mg MPH (n = 4) [40]; Panel B: Data represent model simulated (line) and observed (circles) plasma concentrations of MPH after two repeated dosing with 10 mg MPH, taken 5 h apart (n = 18) [43]; Panel C: Data represent model simulated (line) and observed (circles) plasma concentrations of d -MPH after oral dosing with 40 mg of MPH (n = 24) [39]; Panel D: Data as described for Panel A obtained after oral dosing with 40 mg MPH (n = 6) [42]; Panel E: Data represent model simulated (lines) and observed plasma concentrations of d -MPH (•) and d -RA(▴) after oral dosing with 20 mg d -MPH (n = 15) [41].…”