Delayed-release And Extended-release Methylphenidate Research Articles

Clinically Meaningful Improvements in Early Morning and Late Afternoon/Evening Functional Impairment in Children with ADHD Treated with Delayed-Release and Extended-Release Methylphenidate

Objective: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior–Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful. Method: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression–Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated. Results: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all p < .05). Conclusion: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

A Post Hoc Comparison of Prior ADHD Medication Dose and Optimized Delayed-release and Extended-release Methylphenidate Dose in a Pivotal Phase III Trial

PurposeHLD200 is the first evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) designed to delay initial release of MPH and provide treatment effects throughout the day and into the evening for individuals with attention-deficit/hyperactivity disorder (ADHD). Because DR/ER-MPH is uniquely absorbed in the colon, it cannot be substituted for other ADHD medications on a milligram-per-milligram basis. To provide clinicians with a target dose range for DR/ER-MPH when transitioning patients from a prior ADHD medication, dose conversion ratios (DCRs) between prior medication doses and optimized doses of DR/ER-MPH were determined post hoc from a pivotal Phase III study of children (aged 6–12 years) with ADHD. MethodsDR/ER-MPH doses were optimized over a 6-week open-label period. DCRs were calculated between optimized doses of DR/ER-MPH at week 6 and prior stable doses of ADHD medication. FindingsMean DCRs ranged from 1.8 to 4.3 for optimized DR/ER-MPH dose versus previous stable dose for individuals taking an extended-release stimulant monotherapy. DCRs for those taking an immediate-release stimulant monotherapy ranged from 4.7 to 6.0. ImplicationsIn a Phase III trial of children with ADHD, optimized doses of DR/ER-MPH were higher than doses of prior ADHD medications, but the adverse event profile was consistent with that of other MPHs. Higher DCRs compared with those predicted by bioavailability differences are consistent with a predicted dose-dependent duration of effect for DR/ER-MPH: with increasing doses, absorption is extended but with an attenuated increase in Cmax compared with MPH formulations absorbed in the upper bowel. These data may help guide clinicians to optimize DR/ER-MPH doses. ClinicalTrials.gov identifier: NCT02493777.

Improvement in Functional Impairment During the Early Morning and Late Afternoon/Evening Bookends of the Day: Data from Two Phase 3 Trials of Evening-Dosed Delayed-Release and Extended-Release Methylphenidate in Children with ADHD

Purpose: Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) which uses the DELEXIS® drug delivery technology to delay initial drug release by 8–10 hours, providing onset of treatment effect upon awakening and lasting into the evening. Herein, we report clinician-rated assessments of functional impairment based on parent interview during the early morning and late afternoon/evening in children with attention-deficit/hyperactivity disorder (ADHD) from two pivotal, multicenter, phase 3 trials of DR/ER-MPH. Methods: HLD200-107 (NCT02493777) was a placebo-controlled laboratory classroom trial in children (6–12 years) with ADHD. DR/ER-MPH was titrated to …

Model-Based Approach for Establishing the Predicted Clinical Response of a Delayed-Release and Extended-Release Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder.

HLD200 is an evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) that provides a consistent delay in initial drug release to target onset of therapeutic effect from awakening and maintain it into the evening. Building on a modeling framework established with other extended-release methylphenidate formulations, pharmacokinetic (PK) and PK/pharmacodynamic (PD) models for DR/ER-MPH were developed to describe the time course of effect in response to a range of doses and administration times. Using available PK data from healthy adults, a population PK model was developed using a 1-compartment model with a time-varying absorption rate described by a single Weibull function. A PK/PD model was then developed using Swanson, Kotkin, Agler, M-Flynn, and Pelham combined scores from a phase 3 trial of children with attention-deficit/hyperactivity disorder and simulated plasma concentration-time data. Simulations using the PK/PD model were performed for doses of 60, 80, and 100 mg of DR/ER-MPH, administered 4 to 14 hours before the classroom day. The PK/PD model predicts that DR/ER-MPH produces a clinical response from early morning into the late afternoon or evening, with increased duration of response occurring with increasing doses. Furthermore, the PK/PD model predicts that maximal clinical effect is achieved with DR/ER-MPH administered 12 hours before the start of the classroom day. Model-predicted duration of benefit with DR/ER-MPH is consistent with trial data documenting improvements in functional impairment during the early morning and evening. This model may facilitate dosage optimization by predicting changes in clinical benefit with dose and administration time adjustment.

Clinical Responses and Symptomatic Remissions Achieved With Delayed-Release and Extended-Release Methylphenidate in Children with ADHD

Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) designed to provide treatment effect from the time of waking and throughout the day. A pivotal phase 3 study of DR/ER-MPH in children with ADHD demonstrated significant improvements in ADHD symptoms and functional impairment, with ADHD symptoms measured by the ADHD Rating Scale-IV (ADHD-RS-IV) in the 6-week, open-label, treatment-optimization phase of the study (ClinicalTrial NCT02493777). This post hoc analysis sought to determine the clinical significance of these findings by applying established clinical thresholds of response to the ADHD-RS-IV scores reported in the trial.

6.48 CLINICAL RESPONSES AND SYMPTOMATIC REMISSIONS ACHIEVED WITH DELAYED-RELEASE AND EXTENDED-RELEASE METHYLPHENIDATE IN CHILDREN WITH ADHD

Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) designed to provide treatment effect from the time of waking and throughout the day. A pivotal phase 3 study of DR/ER-MPH in children with ADHD demonstrated significant improvements in ADHD symptoms and functional impairment, with ADHD symptoms measured by the ADHD Rating Scale-IV (ADHD-RS-IV) in the 6-week, open-label, treatment-optimization phase of the study (ClinicalTrial NCT02493777). This post hoc analysis sought to determine the clinical significance of these findings by applying established clinical thresholds of response to the ADHD-RS-IV scores reported in the trial.

6.51 ACHIEVEMENT AND MAINTENANCE OF NORMALIZED LEVELS OF EARLY MORNING AND LATE AFTERNOON/EVENING FUNCTIONAL IMPAIRMENT WITH DELAYED-RELEASE AND EXTENDED-RELEASE METHYLPHENIDATE (DR/ER-MPH) IN CHILDREN WITH ADHD: POST HOC ANALYSES OF BEFORE-SCHOOL FUNCTIONING

In a pivotal phase 3 trial in children (ages 6–12 years) with ADHD, 1 week of double-blind (DB) treatment with evening-dosed HLD200, a delayed-release and extended-release methylphenidate (DR/ER-MPH), resulted in significant improvements in early morning and late afternoon/evening functional impairment versus placebo (PBO), as measured by the validated Parent Rating of Evening and Morning Behavior Scale–Revised (PREMB-R), morning (AM) and evening (PM) subscales, respectively. Substantial improvements in functional impairment over the preceding 6-week, open-label (OL) treatment-optimization phase also were noted by PREMB-R AM/PM and the validated Before School Functioning Questionnaire (BSFQ). In this post hoc analysis, age-adjusted, norm-referenced cutoffs, determined from a representative sample group of 1200 US youth (ages 6–17 years), were applied to BSFQ, PREMB-R AM, and PREMB-R PM scores to interpret changes in functional impairment severity levels (screening risk: mild, moderate, and severe) following OL and DB phases of the pivotal phase 3 trial (ClinicalTrial NCT02493777).

2.31 Effect of Delayed-Release and Extended-Release Methylphenidate (DR/ER-MPH) on All-Day and Early Morning ADHD-Related Symptoms: Analysis of ADHD-Rating Scale-IV and ADHD-AM-Rating Scale Items From a Phase 3 Trial

2.31 Effect of Delayed-Release and Extended-Release Methylphenidate (DR/ER-MPH) on All-Day and Early Morning ADHD-Related Symptoms: Analysis of ADHD-Rating Scale-IV and ADHD-AM-Rating Scale Items From a Phase 3 Trial

2.23 Efficacy and Safety of Delayed-Release and Extended-Release Methylphenidate (DR/ER-MPH) in Children With ADHD: Results From a Pivotal Phase 3 Classroom Trial

2.23 Efficacy and Safety of Delayed-Release and Extended-Release Methylphenidate (DR/ER-MPH) in Children With ADHD: Results From a Pivotal Phase 3 Classroom Trial