Assessment of Pharmacokinetics and Pharmacodynamic Effects Related to Abuse Potential of a Unique Oral Osmotic‐Controlled Extended‐Release Methylphenidate Formulation in Humans

Abstract

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.

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

“…The calibrated adult human oral model was first evaluated against plasma d -MPH concentration time course data collected in healthy adults administered a single oral dose of 50 and 90 mg MPH [34], a dose level slightly higher than the doses (20–40 mg) used for model calibration (Table S1). The calibrated model provided a good prediction of plasma d -MPH kinetic behaviors, except that plasma d -MPH concentrations were slightly overestimated at 12 h within a factor of 2–3 for both dose groups (Figure 10A).…”

“…Panel A: Data represent model simulated (solid line, 90 mg MPH and dashed line, 50 mg MPH) and observed (circles) plasma concentrations of d -MPH after oral dosing with 90 mg (•) and 50 mg(○) MPH (n = 49) [34]; Panel B: Data represent model simulated (line) and observed (circles) plasma concentrations of d-MPH (•) after two repeated oral dosing with 30 mg/kg MPH, taken 6 h apart (n = 28) [35]; Panel C: Data represent model simulated (line) and observed (circles) plasma concentrations (○, test formulation; •, reference formulation) of MPH after oral dosing with 20 mg MPH (n = 20) [36]; Panel D: Data represent model simulated (line) and observed plasma concentrations of MPH (•) and RA (▴) after three repeated oral dosing with 5 mg/kg MPH, taken 4 h apart (n = 35) [37].…”

“…Pharmacokinetic data sets used to evaluate the adult human model were oral dosing studies [20], [28], [34]–[37]. The first kinetic studies used for testing the model were time courses of plasma d-MPH concentrations in healthy adults following a single oral dose of 50 or 90 mg MPH (n = 49) [34] and repeated oral doses of 30 mg MPH (n = 28) [35].…”

“…The first kinetic studies used for testing the model were time courses of plasma d-MPH concentrations in healthy adults following a single oral dose of 50 or 90 mg MPH (n = 49) [34] and repeated oral doses of 30 mg MPH (n = 28) [35]. The second kinetic studies used for model evaluation were time courses of plasma MPH concentrations in healthy adults given a single oral dose of 20 mg MPH (n = 20) [36] and repeated oral doses of 5 mg MPH (n = 35), for which plasma RA concentrations were also determined [37].…”

The abuse potential of medications for attention-deficit/hyperactivity disorder: Recent advances in our understanding

“…Similarly, long-acting stimulants are thought to have a lower abuse potential than immediate-release formulations. In a double-blind, placebo-controlled, randomized, fi ve-period crossover study of 49 healthy subjects with a history of occasional stimulant misuse (with oral administration), immediate-release methylphenidate had more rapid absorption and time to peak concentration than a long-acting formulation [34]. In addition, a low dose (50 mg) of the intermediate-release formulation was associated with a higher subjective effect than a high dose (108 mg) of the long-acting form.…”