Michelle D Po1, Roberto Gomeni2, Bev Incledon3. 1. Dr. Po is with Highland Therapeutics Inc. in Toronto, Ontario, Canada. 2. Dr. Gomeni is with PharmacoMetrica France in La Fouillade, France and is an Adjunct Professor with the Division of Pharmacotherapy and Experimental Therapeutics in the UNC Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill in Chapel Hill, North Carolina. 3. Dr. Incledon is with Ironshore Pharmaceuticals & Development, Inc. in Grand Cayman, Cayman Islands.
Abstract
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.
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.
Authors: Laurence L Greenhill; Steven Pliszka; Mina K Dulcan; William Bernet; Valerie Arnold; Joseph Beitchman; R Scott Benson; Oscar Bukstein; Joan Kinlan; Jon McClellan; David Rue; Jon A Shaw; Saundra Stock Journal: J Am Acad Child Adolesc Psychiatry Date: 2002-02 Impact factor: 8.829
Authors: Mark L Wolraich; Joseph F Hagan; Carla Allan; Eugenia Chan; Dale Davison; Marian Earls; Steven W Evans; Susan K Flinn; Tanya Froehlich; Jennifer Frost; Joseph R Holbrook; Christoph Ulrich Lehmann; Herschel Robert Lessin; Kymika Okechukwu; Karen L Pierce; Jonathan D Winner; William Zurhellen Journal: Pediatrics Date: 2019-10 Impact factor: 7.124
Authors: R Gomeni; Fmm Bressolle-Gomeni; T J Spencer; S V Faraone; L Fang; A Babiskin Journal: Clin Pharmacol Ther Date: 2017-09-19 Impact factor: 6.875