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Objective: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment., Methods: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T -scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated., Results: In HLD200-107 ( N  = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 ( p  < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group ( n  = 81) versus placebo ( n  = 80; 3.11 vs. 4.08; p  = .0053). T -scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported., Conclusion: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T -scores., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: VKA: Advisory Board/Consultant—Ironshore, Neos, Rho, Shire; Speakers Bureau—Ironshore Pharmaceuticals Inc., Lundbeck/Takeda. FAL: Consultant, Speaker, and/or Research Support—Cingulate, Corium, Eli Lilly, GSK, Ironshore, Neos, Novartis, Noven, Pfizer, Rhodes, Shionogi, Shire, Sunovion, Supernus, Tris. ACC: Research Support—Acadia, Akili Interactive Labs, Allergan, Arbor Pharmaceuticals, LLC, Axial, Cingulate, Corium, Emalex, Forest Laboratories, Ironshore, KemPharm, Inc., Lumos, Neos Therapeutics, Neurocentria, Otsuka America Pharmaceutical, Inc., Purdue Pharma, Rhodes Pharmaceuticals, Servier, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda Pharmaceutical Company Ltd., Tris Pharma, Advisory Board—Adlon, Akili Interactive Labs, Arbor Pharmaceuticals, LLC, Cingulate Therapeutics, Otsuka America Pharmaceutical, Inc., Pfizer, Purdue Pharma, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda Pharmaceutical Company Ltd., Tris Pharma; Consultant—Arbor Pharmaceuticals, LLC, Aytu, Attentive Therapeutics, Corium, Ironshore, KemPharm, Inc., Lumos, Neos Therapeutics, Neurocentria, ., Purdue Pharma, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Tris Pharma; Speakers Bureau—Ironshore, Takeda Pharmaceutical Company Ltd., Tris Pharma; Writing Support—Arbor Pharmaceuticals, LLC, Ironshore, Neos Therapeutics, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Takeda Pharmaceutical Company Ltd., Tris Pharma. MDP, CLU, LC, and BI: Employees—Ironshore. FRS: Employee—Ironshore; Advisory Board/Board of Directors—P2D Bioscience.

Delayed-release and extended-release methylphenidate hydrochloride (JORNAY PM®) is a novel capsule formulation of methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder in patients 6 years and older. In this paper, we develop a Level A in vitro-in vivo correlation (IVIVC) model for extended-release methylphenidate hydrochloride to support post-approval manufacturing changes by evaluating a point-to-point correlation between the fraction of drug dissolved in vitro and the fraction of drug absorbed in vivo. Dissolution data from an in vitro study of three different release formulations: fast, medium, and slow, and pharmacokinetic data from two in vivo studies were used to develop an IVIVC model using a convolution-based approach. The time-course of the drug concentration resulting from an arbitrary dose was considered as a function of the in vivo drug absorption and the disposition and elimination processes defined by the unit impulse response function using the convolution integral. An IVIVC was incorporated in the model due to the temporal difference seen in the scatterplots of the estimated fraction of drug absorbed in vivo and the fraction of drug dissolved in vitro and Levy plots. Finally, the IVIVC model was subjected to evaluation of internal predictability. This IVIVC model can be used to predict in vivo profiles for different in vitro profiles of extended-release methylphenidate hydrochloride., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Delayed-release/extended-release methylphenidate (DR/ER-MPH) (formerly HLD200) is an evening-dosed agent used for the treatment of attention-deficit/hyperactivity disorder. Postmarketing surveillance data from approximately 74,000 patients exposed to DR/ER-MPH (up to June 17, 2022) were reported and compared with the open-label, treatment-optimization phase of a Phase III clinical trial to derive possible learnings on how to approach adverse events (AEs) that emerge during dose titration., Methods: An analysis of AEs spontaneously reported to Ironshore in postmarketing surveillance included, where available, age, dose, timing, and discontinuations. Data were summarized using descriptive statistics., Findings: A total of 395 children, adolescents, and adults reported 601 AEs in postmarketing surveillance. Five AEs were classified as serious. AEs preceded drug use discontinuation in 172 patients. Many AEs occurred early (52% were reported within 30 days) and at lower doses (54% were reported at 20 to 40 mg), similar to the trial data. Reported AEs included those similar in type but orders of magnitude lower in number than those from the clinical trial., Implications: No new safety concerns were revealed in this real-world setting compared with the safety profile identified in DR/ER-MPH trial data. In real-world practices, clinicians tended to discontinue DR/ER-MPH treatment after AE onset, whereas trial investigators continued to optimize treatment and found that AEs were generally tolerable, suggesting that health care practitioners may consider developing strategies to manage tolerability issues with DR/ER-MPH treatment on AE emergence rather than immediately discontinuing use of the drug to provide optimal therapeutic benefit., Clinicaltrials: gov identifier: NCT02493777., Competing Interests: Declaration of Competing Interest M.A.K. is a speaker and/or adviser for Abbvie, Alefia Cannabis, Allergan, Bausch Health, Biron, Canopy, Eisai, Elvium, Lundbeck, Janssen, Eli Lilly, Novartis, Merck, Otsuka, Pfizer, Purdue, Sante Cannabis, Sunovion, Takeda, and Tilray. He has also supported clinical trials and/or research studies for Abbvie, Alefia, Biron, Canopy, Lundbeck, Janssen, Eli Lilly, Pfizer, and Takeda. M.A.K. did not receive remuneration for authoring this manuscript, and he is not a consultant nor has he received research funding from Ironshore. V.O., M.D.P., C.L.U., and B.I. are employees of Ironshore. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Most stimulants used to treat attention-deficit/hyperactivity disorder are administered in the morning and absorbed in the upper gastrointestinal tract. DR/ER-MPH (formerly HLD200), an evening-dosed delayed-release and extended-release methylphenidate, is predicted to be absorbed in the proximal colon. The pharmacokinetic (PK) profile of DR/ER-MPH is characterized by an 8- to 10-hour delay in initial methylphenidate absorption and a subsequent gradual increase in plasma concentration, followed by a slow decline. To examine the relationship of absorption site to pharmacokinetics, the DR/ER-MPH formulation was altered to release methylphenidate in the small intestine and distal colon. The 3 formulations were administered in an open-label, 3-way, crossover study in healthy adults (N = 18). Compared with the small intestine formulation, the PK profile of the proximal colon (DR/ER-MPH) formulation exhibited a longer delay before initial methylphenidate absorption, decreased peak methylphenidate concentration, increased time to peak concentration, and decreased bioavailability; these characteristics were amplified in the distal colon formulation. Safety profiles fell within the expectations for methylphenidate products. Modeled PK profiles were similar between the small intestine formulation and a morning-dosed extended-release methylphenidate (both predicted to release methylphenidate in the upper gastrointestinal tract), providing additional evidence that the PK profile of DR/ER-MPH is shaped by colonic absorption., (© 2022 Ironshore Pharmaceuticals & Development, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: Extended-release methylphenidate (ER-MPH) formulations used to treat attention deficit hyperactivity disorder (ADHD) have complex pharmacokinetic (PK) profiles, resulting from differing ratios of immediate-release and extended-release components and/or their site of absorption. This study aimed to evaluate the smoothness of PK curves of ER-MPHs., Design: The integral of the second derivative squared was evaluated for modeled PK curves, with smaller values indicating a smoother curve. The calculated smoothness of each PK curve was normalized by dividing by Cmax 2 to derive a normalized smoothness parameter appropriate across the dose range of each formulation. Calculations used modeled PK curves from 100mg delayed-release and ER-MPH (DR/ER-MPH), 54mg osmotic release oral system MPH (OROS MPH), 60mg MPH controlled-release delivery (MPH CD), 60mg ER-MPH oral suspension (MEROS), 20mg ER dexmethylphenidate (d-MPH ER), and 60mg multilayer-release MPH (MLR-MPH)., Results: The Cmax2-normalized smoothness value was consistent across DR/ER-MPH doses, allowing for relevant comparisons across formulations. Normalized smoothness values differed widely; the lowest normalized smoothness was 0.05 with DR/ER-MPH and ranged up to 9.56 with d-MPH ER., Conclusion: DR/ER-MPH demonstrated a smoother PK profile compared to the highest dose of other ER-MPH formulations. While the benefits of a smooth PK profile remain to be tested clinically, having fewer peaks and troughs has been hypothesized to reduce waxing and waning of therapeutic effects throughout the day, and more gradual changes in MPH plasma levels have been hypothesized to lower the risk of likeability and potentially abate afternoon symptom rebound., Competing Interests: DISCLOSURES: Dr. Po is an employee of Highland Therapeutics Inc., the parent company of Ironshore Pharmaceuticals & Development, Inc. Dr. Gomeni is a paid consultant for Ironshore Pharmaceuticals & Development, Inc.; Sunovion Pharmaceuticals, Inc.; Supernus Pharmaceuticals, Inc.; Teva Branded Pharmaceutical Products R&D, Inc.; Tris Pharma; Biomedical Science Institutes, Singapore; Nanomi BV, the Netherlands; Laboratorios Liconsa SA, Spain; Recordati Rare Diseases, Italy; 4SC AG, Germany; General Hospital Corporation, Boston, Massachusetts; and UCB Biopharma SPRL. Dr. Incledon is an employee of Ironshore Pharmaceuticals & Development, Inc., (Copyright © 2022. Matrix Medical Communications. All rights reserved.)

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.