Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data (original) (raw)
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Archives of General Psychiatry, 2003
The duration of action of the immediaterelease formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance.
BMC Psychiatry, 2013
Background: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed. The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. Methods: A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Results: Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Conclusions: Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and preschool children and the impact of comorbidities and symptom severity on treatment response.
PEDIATRICS, 2004
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, doubledummy, 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 ϳ CON (PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD ϳ CON > PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON > MCD ϳ 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 treatmentemergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed:
Journal of Developmental & Behavioral Pediatrics, 2001
Objective. Methylphenidate (MPH), the most commonly prescribed drug for attention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple daily doses. The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance. Previous long-acting stimulants and preparations have shown effects equivalent to twicedaily dosing of MPH. This study tests the efficacy and duration of action, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12 hours and therefore be equivalent to 3-times-daily dosing.
CNS drugs, 2014
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioural disorder with onset during childhood. It affects a child's development, both at home and at school, and impacts on social, emotional and cognitive functioning, in both the home and the school environment. Untreated ADHD is very often associated with poor academic achievement, low occupational status, increased risk of substance abuse and delinquency. Current practice guidelines recommend a multimodal approach in the treatment of ADHD, which includes educational, behavioural and mental health interventions, and pharmacological management. Stimulant medications, including methylphenidate (MPH) and amphetamine products, are recommended as first-line pharmacotherapy in the treatment of ADHD. The choice of stimulant is influenced by several factors; the most influential factor is the duration of action. Long-acting medication provides benefits long after school and work. It also increases the likelihood of o...
Pediatric Drugs, 2003
Ritalin ® LA™ (20mg) to the starting dose of Concerta ® (18mg), in a laboratory school setting for the duration of an entire school day. Secondary objectives were to compare Ritalin ® LA™ 20mg with Concerta ® 36mg, and Ritalin ® LA™ and both Concerta ® doses versus placebo across the school day. Methods: Thirty-six children (29 males, 7 females), aged 6-12 years, with attention deficit hyperactivity disorder, previously stabilized on methylphenidate (MPH), completed this four-way, randomized, single-blind crossover, analog classroom study. Patients were evaluated on day 0 and randomized to receive treatment on days 7, 14, 21, and 28 (Ritalin ® LA™ 20mg, Concerta ® 18mg, Concerta ® 36mg, or placebo). Results: Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale (SKAMP)-attention: The effect of Ritalin ® LA™ 20mg across the morning was statistically different from that of Concerta 18mg and 36mg, as demonstrated by the change in the area under the curve (AUC) during the first 4 hours (0-4) from pre-dose. AUC(0-4) for Ritalin ® LA™ was-2.48 versus-1.36 for Concerta ® 18mg (p = 0.015), and-1.55 for Concerta ® 36mg (p = 0.043). AUC(0-8) change from pre-dose for Ritalin ® LA™ was-4.48 versus-2.72 for Concerta ® 18mg (p = 0.074), and-3.24 for Concerta ® 36mg (p = 0.208). SKAMP-deportment: AUC(0-4) for Ritalin ® LA™ was-1.67 compared with-0.28 for Concerta ® 18mg (p < 0.001), and-0.55 for Concerta ® 36mg (p = 0.004). AUC(0-8) change from pre-dose for Ritalin ® LA™ was-2.81 compared with-0.82 for Concerta ® 18mg (p = 0.018), and-1.34 for Concerta ® 36mg (p = 0.078). Combined: Mean AUC(0-4) change from pre-dose for Ritalin ® LA™ was-2.05 compared with-0.78 for Concerta ® 18mg (p < 0.001),-1.01 for Concerta ® 36mg (p = 0.003). The mean AUC(0-8) change from pre-dose for Ritalin ® LA™ was-3.58 compared with-1.70 for Concerta ® 18mg (p = 0.010),-2.22 for Concerta ® 36mg (p = 0.061). Math test-attempted: Mean pre-dose score for Ritalin ® LA™ was about 73 compared with 74, 90, and 81 for Concerta ® 18mg, 36mg, and placebo, respectively. Mean AUC(0-8) change from pre-dose for Ritalin ® LA™ was 202 compared with 115 for Concerta ® 18mg (p = 0.135), 137 for Concerta ® 36mg (p = 0.265). Math test-correct: Mean pre-dose score for Ritalin ® LA™ was 68 compared with 64, 78, and 76 for Concerta ® 18mg, 36mg, and placebo, respectively. Mean AUC(0-8) change from pre-dose for Ritalin ® LA™ was 183 compared with 100 for Concerta ® 18mg (p = 0.144), and 117 for Concerta ® 36mg (p = 0.245). 1 The use of tradenames is for product identification purposes only and does not imply endorsement.
Journal of Attention Disorders, 2021
To evaluate the efficacy, safety, and duration of action of the once-daily extended-release methylphenidate formulation PRC-063 for the treatment of ADHD in an adult laboratory classroom (ALC). Method: After dose optimization with PRC-063 over 7 weeks, adults with ADHD were randomized to 1 week of double-blind treatment with PRC-063 or placebo that ended with an ALC evaluation. The primary outcome measure was Permanent Product Measure of Performance-Total (PERMP-T) score. Results: Of 288 subjects enrolled, 221 completed the ALC visit. PERMP-T score was significantly higher for PRC-063 versus placebo at every assessment from 1 to 16 hours post-dose at the ALC visit and when averaged over 16 hours post-dose (least-squares mean difference 16.3, 95% confidence interval 7.6-24.9). The most frequent adverse events during dose optimization were headache, decreased appetite, and insomnia. Conclusion: PRC-063 provided rapid and sustained symptom relief in adults with ADHD and was well tolerated. NCT03618030.
Psychological medicine, 2004
Data on the efficacy and safety of methylphenidate in adults with attention deficit/ hyperactivity disorder (ADHD) are lacking in Europe. This study was undertaken to report on the efficacy and safety of methylphenidate in an adult out-patient population with ADHD, and to compare results with US data. A double-blind randomized cross-over trial comparing methylphenidate and placebo in 45 adults with ADHD with childhood onset was performed in a dose-titration design. Methylphenidate was titrated from 0.5 mg/kg per day in week 1 up to 1.0 mg/kg per day in week 3. Response rates using methylphenidate varied between 38 and 51%, and using placebo between 7 and 18% (p<0.05), depending on outcome measure used. Although the overall percentage of subjects having any side effect on both methylphenidate and placebo was rather high, side effects on methylphenidate over and above those on placebo were few and mild. Methylphenidate proves to be an effective and well tolerated treatment for symp...