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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

PURPOSE/BACKGROUND: 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 establishe...

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Autores principales: Gomeni, Roberto, Komolova, Marina, Incledon, Bev, Faraone, Stephen V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343180/
https://www.ncbi.nlm.nih.gov/pubmed/32590405
http://dx.doi.org/10.1097/JCP.0000000000001222
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author Gomeni, Roberto
Komolova, Marina
Incledon, Bev
Faraone, Stephen V.
author_facet Gomeni, Roberto
Komolova, Marina
Incledon, Bev
Faraone, Stephen V.
author_sort Gomeni, Roberto
collection PubMed
description PURPOSE/BACKGROUND: 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. METHODS/PROCEDURES: 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. FINDINGS/RESULTS: 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. IMPLICATIONS/CONCLUSIONS: 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.
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spelling pubmed-73431802020-08-05 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 Gomeni, Roberto Komolova, Marina Incledon, Bev Faraone, Stephen V. J Clin Psychopharmacol Original Contributions PURPOSE/BACKGROUND: 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. METHODS/PROCEDURES: 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. FINDINGS/RESULTS: 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. IMPLICATIONS/CONCLUSIONS: 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. Lippincott Williams & Wilkins 2020 2020-06-25 /pmc/articles/PMC7343180/ /pubmed/32590405 http://dx.doi.org/10.1097/JCP.0000000000001222 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Contributions
Gomeni, Roberto
Komolova, Marina
Incledon, Bev
Faraone, Stephen V.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Contributions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343180/
https://www.ncbi.nlm.nih.gov/pubmed/32590405
http://dx.doi.org/10.1097/JCP.0000000000001222
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