A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory School (The Comacs Study)

摘要

Objective. The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration.Methods. This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs.Results. The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment × session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment × session interactions suggested 4 patterns of efficacy across the day: 1) PLA MCD ～ CON (PLA superiority) immediately after dosing; 2) MCD CON PLA during the morning (MCD superiority); 3) MCD ～ CON PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON MCD ～ PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose × treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period.2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at