Usability of a novel digital medicine system in adults with schizophrenia treated with sensor-embedded tablets of aripiprazole.

OBJECTIVE: Digital medicine system (DMS) is a novel drug-device combination that objectively measures and reports medication ingestion. The DMS consists of medication embedded with an ingestible sensor (digital medicine), a wearable sensor, and software applications. This study evaluated usability of the DMS in adults with schizophrenia rated by both patients and their health care providers (HCPs) during 8-week treatment with prescribed doses of digital aripiprazole. METHODS: Six US sites enrolled outpatients into this Phase IIa, open-label study (NCT02219009). The study comprised a screening phase, a training phase (three weekly site visits), and a 5-week independent phase. Patients and HCPs independently rated usability of and satisfaction with the DMS. RESULTS: Sixty-seven patients were enrolled, and 49 (73.1%) patients completed the study. The mean age (SD) of the patients was 46.6 years (9.7 years); the majority of them were male (74.6%), black (76.1%), and rated mildly ill on the Clinical Global Impression - Severity scale (70.1%). By the end of week 8 or early termination, 82.1% (55/67) of patients had replaced the wearable sensor independently or with minimal assistance, based on HCP rating. The patients used the wearable sensor for a mean (SD) of 70.7% (24.7%) and a median of 77.8% of their time in the trial. The patients contacted a call center most frequently at week 1. At the last visit, 78% (47/60) of patients were somewhat satisfied/satisfied/extremely satisfied with the DMS. CONCLUSION: A high proportion of patients with schizophrenia were able to use the DMS and reported satisfaction with the DMS. These data support the potential utility of the DMS in clinical practice.

A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.

Outcomes of switching directly to oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

BACKGROUND: The Evaluate Patient OutComes (ClinicalTrials.gov Identifier: NCT01216072) study was conducted in North America to assess patient- and physician-reported treatment satisfaction in patients with relapsing multiple sclerosis (MS) who received oral fingolimod for 6 months after switching from an injectable disease-modifying therapy (iDMT), without an intervening washout. METHODS: In this open-label, multicenter study, patients were randomized 3:1 to once-daily fingolimod 0.5mg or iDMT. The primary study objective was to evaluate differences in satisfaction measured using the Treatment Satisfaction Questionnaire for Medication v1.4. RESULTS: Of 1053 patients randomized, 790 patients received fingolimod and 263 patients received iDMT. Treatment satisfaction improved significantly in patients who switched to fingolimod compared with those who continued iDMT. Patients also reported significant improvements in health-related quality of life, reduced depression, and reduced fatigue severity after a switch to fingolimod. No difference between the treatment groups was detected on the Patient Reported Indices for MS Activities scale. The safety profile of fingolimod was consistent with that reported in the pivotal phase 3 studies. The most commonly reported adverse events were more prevalent in patients who switched to fingolimod than in those who continued iDMT (headache: 12% vs 3%; fatigue: 12% vs 6%). No significant relationship between lymphocyte counts and infection rates was observed and there was no evidence of additive immune-system effects, which might be expected when switching to a different class of immunomodulatory therapy with no intervening washout. CONCLUSION: Patients who switched from iDMT to fingolimod had significant improvements in most self-reported outcomes compared with those who continued iDMT.

Extended-release dexmethylphenidate 30 mg/d versus 20 mg/d: duration of attention, behavior, and performance benefits in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study aimed to compare the effects of dexmethylphenidate (D-MPH) extended-release (ER) 30 mg and D-MPH-ER 20 mg on attention, behavior, and performance in children with attention-deficit/hyperactivity disorder. METHODS: In a randomized, double-blind, 3-period-by-3-treatment, crossover study, children aged 6 to 12 years with attention-deficit/hyperactivity disorder stabilized on methylphenidate (40-60 mg/d) or D-MPH (20-30 mg/d) received D-MPH-ER 20 mg/d, 30 mg/d, and placebo for 7 days each (final dose of each treatment period administered in a laboratory classroom). Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Combined (Attention and Deportment) rating scale and Permanent Product Measure of Performance (PERMP) math test assessments were conducted at baseline and 3, 6, 9, 10, 11, and 12 hours postdose. RESULTS: A total of 165 children (94 boys; mean age, 9.6 years) were randomized (162 included in intent-to-treat analyses). Significant improvements were noted for D-MPH-ER 30 mg over D-MPH-ER 20 mg at various late time points on the SKAMP scales (Combined scores at 9, 10, 11, and 12 hours postdose; Attention scores at 10, 11, and 12 hours postdose; deportment scores at 9 and 12 hours postdose). The PERMP math test-attempted and -correct scores (change from predose) were significantly higher with D-MPH-ER 30 mg than with D-MPH-ER 20 mg at 10, 11, and 12 hours postdose. Both D-MPH-ER doses were superior to placebo at all time points. CONCLUSIONS: D-MPH-ER 30 mg was superior to D-MPH-ER 20 mg at later time points in the day, suggesting that higher doses of D-MPH-ER may be more effective later in the day.

Randomized, open-label study to evaluate patient-reported outcomes with fingolimod after changing from prior disease-modifying therapy for relapsing multiple sclerosis: EPOC study rationale and design.

OBJECTIVE: The study to Evaluate Patient OutComes, Safety, and Tolerability of Fingolimod (EPOC; NCT01216072) aimed to test the hypothesis that therapy change to oral Gilenya (Novartis AG, Stein, Switzerland) (fingolimod) improves patient-reported outcomes compared with standard-of-care disease-modifying therapy (DMT) in patients with relapsing multiple sclerosis; safety and tolerability were also assessed. This communication describes the study rationale and design. METHODS: EPOC is a phase 4, open-label, multi-center study conducted in the US and Canada of patients with relapsing forms of multiple sclerosis who are candidates for therapy change. Therapy change eligibility was determined by the treating physician (US patients) or required an inadequate response to or poor tolerance for at least 1 MS therapy (Canadian patients). Patients were randomly assigned in a 3:1 ratio to 6 months of treatment with once-daily oral fingolimod 0.5 mg or standard-of-care DMTs. The primary study end-point was the change from baseline in treatment satisfaction as determined by the global satisfaction sub-scale of the Treatment Satisfaction Questionnaire for Medication. Secondary end-points included changes from baseline in perceived effectiveness and side-effects, and measures of activities of daily living, fatigue, depression, and quality-of-life. A 3-month open-label fingolimod extension was available for patients randomly assigned to the DMT group who successfully completed all study visits. RESULTS: Enrollment has been completed with 1053 patients; the patient population is generally older and has a longer duration of disease compared with populations from phase 3 studies of fingolimod. LIMITATIONS: Inclusion criteria selected for patients with a sub-optimal experience with a previous DMT, limiting the collection of data on therapy change in patients who were satisfied with their previous DMT. CONCLUSIONS: Results of the EPOC study are anticipated in early 2013 and will inform treatment selection by providing patient-centered data on therapy switch to fingolimod or standard-of-care DMTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216072.

A randomized, double-blind study of 30 versus 20 mg dexmethylphenidate extended-release in children with attention-deficit/hyperactivity disorder: late-day symptom control.

The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with attention-deficit/hyperactivity disorder (ADHD) in a 12-hour laboratory classroom setting. In a randomized, double-blind, 3-period × 3-treatment, crossover study, children aged 6 to 12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed ADHD previously stabilized on MPH (40-60 mg/d) or D-MPH (20-30 mg/day) [corrected] were randomized to receive D-MPH-ER 20 mg/day, 30 mg/day, [corrected] or placebo for 7 days each. Primary efficacy measurements were change in the average SKAMP-Combined [corrected] score from predose to 10, 11, and 12 hours postdose [Avg(10-12)] between 30 mg [corrected] and 20 mg D-MPH-ER. Safety was assessed by adverse events, (AEs), [corrected] vital sign monitoring, and ECGs. [corrected] A total of 165 children were randomized, and 162 included in the intent-to-treat analysis. Mean Avg (10-12) change from pre-dose [corrected] in SKAMP-Combined score was significantly greater for D-MPH-ER 30 mg (-4.47) compared with D-MPH-ER 20 mg (-2.02; P = 0.002). Most common adverse events (≥ 3% in any group) were decreased appetite (6.1%, 4.9%, and 0%), headache (4.3%, 4.3%, and 1.9%), abdominal pain (3.7%, 3.1%, and 3.1%), and tachycardia (1.2%, 3.1%, and 0.6%) for D-MPH-ER 30 mg, D-MPH-ER 20 mg, and placebo, respectively). Significantly greater improvement in ADHD symptoms was noted with D-MPH-ER 30 mg compared with D-MPH-ER 20 mg at hours 10 through 12. Tolerability was comparable between doses. Dexmethylphenidate extended-release 30-mg dose may provide further benefit to patients who do not maintain optimal symptom control later in the day with D-MPH-ER 20 mg.

A global measure to assess switching antipsychotic medications in the treatment of schizophrenia.

OBJECTIVES: It is common practice to switch antipsychotic medications in the treatment of patients with schizophrenia to enhance clinical efficacy and/or reduce drug-related side effects. The conventional Clinical Global Impression (CGI) of severity scale is a well-understood measure to track switching effects but does not differentiate between the severity of clinical symptoms and the impact of side effects.. METHODS: We developed a CGI-switch instrument that contains distinct global severity scales for clinical efficacy, safety and/or tolerability, and a third unified (integrated) CGI severity score to assess these interrelated assessments. An integrated Clinical Global Impression of Change was also created to assess global clinical change relative to the initiation of treatment. RESULTS: Interrater reliability conducted as part of a rater-training program for a clinical study (Novartis protocol CIL0522D; clinitrials.gov identifier: CT01207414) revealed high interrater agreement (Cronbach's alpha = 0.945). Data were collected from 1066 CGI assessments during the course of the trial. CGI raters easily grasped the utility of the instrument. The distinction made between efficacy and safety/tolerability facilitated serial tracking of each condition during the course of treatment. CONCLUSION: The modified CGI-switch instrument is a simple, reliable, and practical metric to assess the benefits, if any of switching antipsychotic medications in patients with schizophrenia.

Dexmethylphenidate extended-release capsules in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study compared once-daily dexmethylphenidate extended release (D-MPH-ER) 20 mg/day and placebo over 12 hours in children ages 6 to 12 with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. METHOD: All of the children were stabilized for > or =2 weeks on a total dose (nearest equivalent) MPH 40 mg/day or immediate-release D-MPH 20 mg/day before screening. After a practice day, they received 6 days of D-MPH-ER 20 mg/day or placebo at home, returning on day 7 for one dose. Subjects were evaluated at predose and postdose hours 0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 and then crossed over to the other treatment arm using the identical protocol. The primary efficacy variable was the change from predose in Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale (SKAMP) combined score from 1 to 12 hours. Secondary efficacy variables included SKAMP combined score at 0.5 hours, SKAMP subscale scores, and math test results over 12 hours. RESULTS: Sixty-eight children were randomized, with 67 completing the study. Onset of action was indicated by a significant difference between D-MPH-ER and placebo at 0.5 hour on the SKAMP combined score (p = .001). For efficacy measures, differences from placebo were significant at all points between 0.5 and 12 hours (p < .001 top = .013). CONCLUSIONS: D-MPH-ER provided sustained improvement in attention, deportment, and academic productivity throughout the 12-hour laboratory day.

Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: This multicenter, randomized, fixed-dose, double-blind, placebo-controlled study evaluated efficacy of extended-release dexmethylphenidate (d-MPH-ER) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Randomized adults with ADHD (n=221) received once-daily d-MPH-ER 20 mg, 30 mg, or 40 mg or placebo for 5 weeks. The primary efficacy variable was change from baseline to final visit in DSM-IV ADHD Rating Scale (ADHD-RS) total score. Secondary efficacy parameters included the proportion of patients with improvement>or=30% in ADHD-RS total score and final scores on Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: Of 218 evaluable patients, 184 completed the study. All d-MPH-ER doses were significantly superior to placebo in improving ADHD-RS total scores. Placebo scores improved by 7.9; d-MPH-ER, 20 mg, improved by 13.7 (p=.006); d-MPH-ER, 30 mg, improved by 13.4 (p=.012); and d-MPH-ER, 40 mg, improved by 16.9 (p<.001). Overall distribution of CGI-I ratings at final visit was significantly better with each d-MPH-ER dosage than with placebo. There were no unexpected safety or tolerability concerns, based on experience with racemic methylphenidate (MPH) in adults and dexmethylphenidate (d-MPH) in children. CONCLUSIONS: Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.

Efficacy and safety of dexmethylphenidate extended-release capsules in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The efficacy and safety of dexmethylphenidate extended release (d-MPH-ER) was compared to placebo in pediatric patients with attention-deficit/hyperactivity disorder (ADHD). METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, two-phase study included 97 patients (ages 6-17 years) with DSM-IV-defined ADHD. The study was carried out between 2001 and 2003. After a 2-week evaluation phase, patients were randomized to d-MPH-ER or placebo for 7 weeks. Flexible d-MPH-ER dosing (30 mg/day) was permitted for 5 weeks, then patients remained on their optimal dose during the last 2 study weeks. The primary efficacy measure was change from baseline to final rating in Conners ADHD/DSM-IV Scale-Teacher version (CADS-T) total subscale score. Secondary efficacy variables included changes from baseline to final visit in CADS-T Inattentive and Hyperactive-Impulsive subscale scores, CADS-P DSM-IV total subscale score and Inattentive and Hyperactive-Impulsive subscale scores, Clinical Global Impressions-Improvement (CGI-I) and CGI-Severity (CGI-S) scale scores, and Child Health Questionnaire Parent Form 50 scores. RESULTS: d-MPH-ER improved CADS-T total scores significantly compared with placebo (p <.001), and 67.3% of d-MPH-ER patients were rated much improved or very much improved on CGI-I at final visit versus 13.3% of placebo patients (p <.001). More patients taking d-MPH-ER (49.1%) than placebo (25.5%) spontaneously reported adverse events suspected as drug related. CONCLUSIONS: Once-daily d-MPH-ER was more effective than placebo in the treatment of ADHD in children and adolescents.

Efficacy and duration of effect of extended-release dexmethylphenidate versus placebo in schoolchildren with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to assess changes in symptomatology of attention-deficit/ hyperactivity disorder (ADHD) with extended-release dexmethylphenidate (d-MPHER) versus placebo in a laboratory classroom setting. METHODS: This double-blind, placebo-controlled, crossover study randomized 54 children 6-12 years of age, stabilized on methylphenidate 20-40 mg/day. Patients participated in a practice day, then received 5 days of treatment with d-MPH-ER 20 mg/day or placebo. After a 1-day wash-out, they returned to the classroom and received 1 dose of their assigned treatment. Evaluations occurred predose and at postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12. Children were then crossed over to the alternate treatment, using identical protocol. Primary efficacy variable was the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale (SKAMP)-Combined scores, and primary analysis time point was 1 hour postdose; secondary efficacy variables over 12 hours included SKAMP-Attention and -Deportment scores and written math test results. Safety was assessed by adverse event (AE) recording following each period. Vital signs were recorded at each visit; laboratory tests were conducted at screening and final visit. RESULTS: D-MPH-ER 20 mg/day showed a significant advantage over placebo as early as 1 hour postdose on SKAMP-Combined scores (p < 0.001). When analyzing the entire sample of 54 children, d-MPH-ER maintained significant superiority over placebo from hours 1 through 12 (p-values ranged from < 0.001 to 0.046). D-MPH-ER was well tolerated, with no severe AEs reported. CONCLUSIONS: D-MPH-ER is safe and effective and improves classroom attention, deportment, and performance in children with ADHD.

A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study.

dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.

Efficacy of two long-acting methylphenidate formulations in children with attention- deficit/hyperactivity disorder in a laboratory classroom setting.

OBJECTIVE: The aim of this study was to compare efficacy and safety of two long-acting formulations of methylphenidate (MPH) for attention-deficit/hyperactivity disorder (ADHD) in school-age children. METHODS: Children 6-12 years of age diagnosed with ADHD and stabilized on MPH (20-40 mg/day) participated in a five-way, randomized, placebo-controlled, single-blind, crossover study conducted in a laboratory classroom setting. Children alternately received single doses of extended-release MPH (ER-MPH) 20 and 40 mg, modified-release MPH (OROS-MPH) 18 and 36 mg, and placebo over 6 consecutive weeks. Efficacy was assessed using SKAMP rating subscales and written math tests. Data were examined using between-treatment comparisons of area under the curve (AUC) for change from predose values during hours 0-4, 0-8, 8-12, and 0-12. Safety was assessed. RESULTS: Fifty-three children completed the study. For all efficacy measures, improvements from predose were significantly greater with ER-MPH 40 mg than with OROS-MPH 36 mg in terms of AUC(0-4) (p < or = 0.005), AUC(0-8) (p < or = 0.006), and AUC(0-12) (p < or = 0.035). For most measures, ER-MPH 20 mg was equivalent to both doses of OROS-MPH in AUC(0-4), AUC(0-8), and AUC(0-12). No serious adverse events were reported. CONCLUSIONS: The efficacy of ER-MPH 20 mg is similar to that of OROS-MPH 18 and 36 mg during the first 8 hours postdose. Statistically greater benefits are observed with ER-MPH 40 mg than with OROS-MPH 36 mg and persist through hour 8. Active treatments show comparable efficacy from 8 to 12 hours postdose. Both doses of each MPH formulation are well tolerated.

Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day.

OBJECTIVES: The primary objective was to compare the differences in clinical efficacy of the starting dose of 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 RitalinLA 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). SAFETY: One patient from each treatment group experienced a single mild adverse event that included abdominal pain, nausea, and dyspnea. CONCLUSION: While both Ritalin LA and Concerta were shown to be effective, the different release profiles of each formulation can result in distinct differences between the effects on measures of attention and deportment.

Pharmacokinetics of methylphenidate after oral administration of two modified-release formulations in healthy adults.

OBJECTIVE: To compare the rate and extent of absorption of DL-threo-methylphenidate (MPH) from two modified-release MPH formulations at their respective recommended starting doses in healthy adult volunteers. DESIGN: Open-label, randomised, crossover, bioavailability study. PARTICIPANTS: Twenty healthy adult male and female volunteers. METHODS: Subjects received single doses of two modified-release formulations of MPH, a 20mg capsule (Ritalin) LA) and an 18 mg tablet (Concerta). A total of 19 plasma samples was collected over 24 hours, and MPH plasma concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS). These values were used to calculate standard noncompartmental pharmacokinetic parameters describing the rate (peak concentration and time to peak concentration) and extent (area under the concentration-time curve, AUC) of absorption of the two formulations. The relative bioavailability of the two drugs was assessed using a 90% confidence interval, based on the lower and upper endpoints of the confidence interval for the ratios of the geometric means (log transformed) being within the 0.80-1.25 equivalence criterion. RESULTS: Nineteen subjects, ten male and nine female, aged 21-34 years completed both treatment phases of the study. The Ritalin LA formulation displayed a distinctly biphasic pharmacokinetic profile, with mean initial peak plasma concentration of 7 microg/L at an average of 2.1 hours after administration and a second peak of 9.3 microg/L occurring at 5.6 hours. In contrast, the profile of the Concerta formulation rapidly reached an initial plateau concentration of 3.4 microg/L at 3.3 hours after administration and a second mean plateau concentration of 5.9 microg/L approximately 6 hours after administration. Substantially more MPH was absorbed from Ritalin LA than from Concert over the first 4 hours; the respective AUC(4) values were 18.5 and 9.3 microg x h/L (p < 0.001). The overall extent of absorption of MPH was similar between the two formulations. Oral clearance was identical between the two dosage forms. CONCLUSIONS: The Ritalin LA formulation exhibited more rapid initial absorption and reached significantly higher peak plasma concentrations compared with the Concerta formulation, although the oral bioavailability of MPH was similar between the two formulations. The Ritalin LA capsule demonstrated a distinctly bimodal plasma concentration-time profile. MPH plasma concentrations resulting from Concerta reached a peak at 6 hours. These results indicate that the recommended starting dose of the Ritalin LA 20 mg capsule formulation provides more rapid absorption and higher peak plasma concentrations than the recommended 18 mg starting dose of the Concerta formulation.