Joseph L. Reiz

Cognitive and Behavioral Effects of Multilayer-Release Methylphenidate in the Treatment of Children with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE The aim of this study was to compare the pharmacodynamics of a new multilayer-release (MLR) formulation methylphenidate (MPH; Biphentin) with immediate-release (IR) MPH (Ritalin) in a double-blind, cross-over, placebo-controlled study in patients with attention-deficit/hyperactivity disorder (ADHD). METHOD Patients were randomized to equivalent doses of MPH as MLR (once per day), IR (twice per day) or placebo. Each treatment was taken for 1 week prior to repeated behavioral and cognitive laboratory evaluations on a single day in each phase of the crossover. RESULTS Two girls and 15 boys 6.8-15.3 years old (mean age 11.3 +/- 2.2 years) participated. Both MLR and IR MPH significantly reduced the Stop Signal Reaction Time (p = 0.0001, p = 0.0005), the Errors of Omission on the Continuous Performance Task (p = 0.0039, p = 0.0001), the IOWA-Conners Inattention/Overactivity Index (p = 0.0001, p = 0.0001), and increased the Clinical Global Impressions (CGI) Efficacy Index (p = 0.0001, p = 0.0017) and reduced the CGI Global Improvement Index (p = 0.0001, p = 0.0006) compared to placebo. Mild adverse events were experienced by 4, 6, and 3 patients on placebo, IR, and MLR MPH, respectively. CONCLUSIONS MLR MPH given once daily produces equivalent improvements in behavioral and cognitive measures, and has a duration of effect at least as long as that of IR MPH given twice daily.

Single‐Dose Pharmacokinetics of Multilayer‐Release Methylphenidate and Immediate‐Release Methylphenidate in Children With Attention‐Deficit/Hyperactivity Disorder

The objective of this study was to compare the single‐dose pharmacokinetics of multilayer‐release and immediate‐release methylphenidate in children with attention‐deficit/hyperactivity disorder. Patients 6‐ to 12‐years‐old with a DSM‐IV diagnosis of attention‐deficit/hyperactivity disorder were randomized to receive multilayer‐release methylphenidate (qd) or immediate‐release methylphenidate (bid) at equivalent doses, with a 14‐day washout between treatments. Plasma samples were collected predosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Pharmacokinetic analysis was conducted on 14 patients (1 female, 13 male; mean age: 9.6 ± 2.5 years [range, 6–12]). The mean dose of methylphenidate received by these patients in both phases of the study was 38.6 mg/d (range, 20–80 mg/d). The relative AUC0–t and Cmax 0–4 ratios for multilayer‐release compared with immediate‐release methylphenidate were 100.8% and 78.8%, respectively. Multilayer‐release methylphenidate produces a biphasic concentration‐time profile, with a rapid initial increase in plasma concentration that is maintained throughout the school day.

A double‐blind randomized dose‐response study comparing daily doses of 5, 10 and 15 mg controlled‐release oxybutynin: balancing efficacy with severity of dry mouth

To assess the efficacy, incidence of dry mouth and overall satisfaction with initial doses of 5, 10 and 15 mg of a new, once‐daily, controlled‐release (CR) form of oxybutynin for treating urge urinary incontinence (UUI).

Comparative bioavailability of single-dose methylphenidate from a multilayer-release bead formulation and an osmotic system: A two-way crossover study in healthy young adults

OBJECTIVE This study was conducted to compare plasma levels of methylphenidate over time with single doses of a multilayer-release (MLR) bead formulation and an osmotic, controlled-release oral delivery system (OROS) of methylphenidate in young adults. METHODS This was a randomized, 2-way crossover study in which healthy, nonsmoking young adults (age 18-25 years) were randomized to receive methylphenidate MLR 20 mg QD or OROS methylphenidate 18 mg QD, with a 7-day washout between treatments. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours after dosing. Analysis of plasma samples was conducted by high-performance liquid chromatography with tandem mass-spectrometry detection. Adverse events were monitored by spontaneous reports, laboratory and biochemistry tests, urinalysis, and physical examinations conducted at screening and at the end of the study. RESULTS Of the 24 subjects originally enrolled, 3 discontinued for personal reasons after the first phase and were not included in the pharmacokinetic analysis. The per-protocol population (11 females, 10 males) had a mean (SD) age of 22 (2) years (range, 19-25 years) and a mean body mass index of 23.6 (3.0) kg/m(2) (range, 19.0-28.5 kg/m(2)). The relative AUC0t and Cmax ratios for the MLR methylphenidate formulation compared with the OROS methylphenidate formulation were 110.88% and 121.84%, respectively. When OROS methylphendate values were dose normalized to 20 mg, the relative AUC0-t and Cmax ratios were 100.72% and 111.82%. The mean Tmax for the 2 formulations was 3.71 (2.03) and 4.96 (2.56) hours. Values were significantly higher with the MLR methylphenidate formulation compared with the OROS methylphenidate formulation for AUC(0-4) (P < 0.001), AUC(0-8) (P < 0.001), AUC(0-12) (P < 0.001), and AUC(4-12) (P = 0.037); the AUC(8-12) was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for C(max0-4) (P < 0.001) and C(max4-12) (P = 0.002). Thirty-seven adverse events occurred in 11 and 10 subjects during receipt of MLR and OROS methylphenidate, respectively. The most commonly reported adverse events in the intent-to-treat population were catheter-site pain, reported by 8 of 24 subjects (33.3%), and headache, reported by 5 of 24 subjects (20.8%). CONCLUSIONS In these healthy young subjects, MLR methylphenidate was associated with a concentration-time profile that resulted in a higher proportion of the administered methylphenidate dose being delivered in the first 4 hours after dosing compared with OROS methylphenidate while maintaining comparable levels of drug in the latter portion of the dosing interval. This led to maintenance of higher mean levels of methylphenidate throughout the day compared with the closest marketed dose of OROS methylphenidate. The 2 formulations are marketed in dissimilar strengths; however, after correction for administered dose, they yielded similar AUC values.

Controlled-release codeine is equivalent to acetaminophen plus codeine for post-cholecystectomy analgesia

PurposeFollowing ambulatory surgery, long-acting analgesics may provide advantages over short-acting analgesics. This study compared controlled-release codeine (CC) and acetaminophen plus codeine (A/C; 300 mg/30 mg) for pain control in the 48-hr period following laparoscopic cholecystectomyMethodsEligible patients were randomized to CC or A/C in a double-blind, double-dummy parallel group study. Unrelieved pain in hospital was treated with fentanyliv bolus. Rain [100 mm visual analogue scale (VAS)] was assessed before the first dose of medication; at 0.5, one, two, three, and four hours post-dose; at discharge; and three times a day for 48 hr. Adverse events were recorded and measures of patient satisfaction were assessed at the end of the study.ResultsEighty-four patients were enrolled in the study; 42 patients in each group. There were no statistically significant differences between CC and A/C treatment. Mean VAS baseline pain was similar in both groups (P = 0.49) and there was no significant difference in the time to onset of analgesia (P = 0.17). At 0.5 hr, the mean VAS pain score was significantly reduced from baseline in both groups (P = 0.0001). The VAS pain scores at discharge were reduced 59% and 56% from baseline, respectively (P = 0.61). There was no difference between treatments in the incidence of adverse events and patients reported similar levels of satisfaction.ConclusionsControlled-release codeine provides an equivalent onset of analgesia, reduction in postoperative pain, and level of patient satisfaction, to acetaminophen plus codeine, over 48 hr following cholecystectomy, with the advantage of less frequent dosing.RésuméObjectifEn chirurgie ambulatoire, les analgésiques postopératoires d’action prolongée peuvent avoir des avantages sur les analgésiques d’action brève. Nous comparons la codéine à libération contrôlée (CC) et une combinaison d’acétaminophène et de codéine (A/C; 300 mg/30 mg) comme analgésique pendant 48 h après une cholécystectomie laparoscopique.MéthodeDes patients admissibles à l’expérimentation ont reçu de la CC ou de l’A/C lors d’une étude à double insu, à double placebo en contrôle parallèle. A l’hôpital, la douleur tenace a été traitée avec des bolus iv de fentanyl. La douleur [échelle visuelle analogique (EVA) de 100 mm] a été évaluée avant la première dose de médicament; à 0,5, une, deux, trois et quatre heures après la dose; au moment du départ et trois fois par pur pendant 48 h. Les événements indésirables ont été notés et des mesures de la satisfaction du patient ont été faites à la fin de l’étude.RésultatsLétude a été réalisée auprès de 84 patients: 42 dans chaque groupe. Il n’y a pas eu de différence statistiquement significative entre les traitements à la CC ou à l’A/C. La douleur initiale moyenne a été similaire dans les deux groupes (P = 0,49) et il n’y a pas eu de différence significative de temps précédant le début de l’analgésie (P = 0,17). À 0,5 h, le score de douleur moyen à l’EVA était significativement réduit dans les deux groupes (P = 0,0001). Les scores à l’EVA au départ de l’hôpital ont été respectivement réduits de 59 % et de 56 % par rapport aux mesures initiales de la douleur (P = 0,61). Aucune différence intergroupe dans l’incidence d’événements indésirables n’a été notée et la satisfaction des patients était comparable d’un groupe à l’autre.ConclusionLa codéine à libération contrôlée offre un délai d’installation de l’analgésie, une réduction de la douleur postopératoire et un niveau de satisfaction équivalents à une combinaison d’acétaminophène et de codéine pendant 48 h après une cholécystectomie, et ce, avec l’avantage d’un dosage moins fréquent.

Pharmacokinetics and Pharmacodynamics of Once‐Daily Controlled‐Release Oxybutynin and Immediate‐Release Oxybutynin

Oxybutynin is used to treat patients with urinary urgency, frequency, and urge incontinence. In this 2‐way, multiple‐dose, crossover study, the pharmacokinetics and pharmacodynamics of once‐daily controlled‐release oxybutynin were compared with immediate‐release oxybutynin. Eighteen healthy male volunteers received one 15‐mg controlled‐release oxybutynin tablet once daily for 5 days or one 5‐mg immediate‐release oxybutynin tablet every 8 hours for 5 days. The washout period between treatments was ≤7 days. The mean steady‐state AUC for oxybutynin following controlled‐release oxybutynin treatment was higher (73.0 ng·h/mL) than following immediate‐release oxybutynin treatment (53.6 ng·h/mL) (P = .0001). The mean Cmax was lower for controlled‐release oxybutynin (5.7 ng/mL) than for immediate‐release oxybutynin (7.5 ng/mL) (P = .0051), with a smaller fluctuation in oxybutynin plasma concentration for controlled‐release oxybutynin (135.6%) than for immediate‐release oxybutynin (319.3%) (P = .0001). Mean stimulated saliva output was greater for controlled‐release oxybutynin, and mean dry mouth severity was less than immediate‐release oxybutynin.

An evaluation of patient and physician satisfaction with controlled-release oxybutynin 15 mg as a one-step daily dose in elderly and non-elderly patients with overactive bladder: results of the STOP study.

Abstract Objective: Evaluate patient and physician satisfaction with a novel formulation of a once-daily controlled-release (CR) oxybutynin (Uromax *Uromax is a registered trade-mark of Purdue Pharma, Pickering, Ontario, Canada) 15-mg tablet as both the initial and maintenance dose in elderly and non-elderly patients with overactive bladder (OAB). Methods: Patients not on anticholinergic treatment for OAB and experiencing urinary incontinence (≥1 episode/week) and micturition frequency (≥8 episodes/day) or urgency (≥1 episode/week) were enrolled in this 4-week, open-label study. Satisfaction, efficacy, mental status and adverse events were evaluated by urologists, gynecologists, urogynecologists and family practitioners. The analyses compared the outcomes in patients <65 and ≥65 years. Clinical trial registration: ISRCTN 19242032. Results: A total of 240 patients enrolled; 111 (46%) were ≥65 years of age. Completion rate was 76.0% (<65) and 62.2% (≥65) (p = 0.0204). Medication was rated as tolerable by 75.2% of patients <65 and 58.6% of patients ≥65 (p = 0.0099). Based on overall satisfaction scores 64.2% (patient scores) and 57.1% (physician scores) of patients were considered ‘successfully treated’ (p = 0.0001 & p = 0.0451). There was a significant reduction in incontinence (64.3%; p = 0.0001), nocturia (38.6%; p = 0.0001) and night-time incontinence (39.7%; p = 0.0436) with no difference between age groups. Total continence was achieved by 29.8% and 47.5% of patients <65 and ≥65, respectively (p = 0.0077). No patients clinically experienced confusion or delirium and only six patients ≥65 had a decrease in MMSE score of ≥3 units, which was not statistically different from patients <65 (p = 0.3112). Dry mouth was the most common adverse event reported by 24.8% of patients <65 and 36.0% of patients ≥65 (p = 0.0584). Limitations of the study include a fixed dosing, no control group and 4-week trial. Conclusion: Patients and physicians were satisfied with CR oxybutynin 15 mg once-daily. Patients tolerated the CR oxybutynin 15 mg as both the initial and maintenance dose and provided significant reductions in incontinence, nocturia and night-time incontinence without a significant change in cognitive status. Total continence rates were significantly superior in patients ≥65 and there was no difference in dry mouth, cognitive status or efficacy in patients <65 and ≥65.

The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment.

Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.

Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.

OBJECTIVE To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users. DESIGN Randomized, blinded, dose ratio escalation study. SETTING Single center. PARTICIPANTS Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3). INTERVENTIONS Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios. MAIN OUTCOME MEASURES Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS). RESULTS Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios. CONCLUSIONS This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.