Model‐Based Approach for Optimizing Study Design and Clinical Drug Performances of Extended‐Release Formulations of Methylphenidate for the Treatment of ADHD

Abstract

Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.

A General Framework for Assessing In vitro/In vivo Correlation as a Tool for Maximizing the Benefit‐Risk Ratio of a Treatment Using a Convolution‐Based Modeling Approach

“…The change from placebo of the SKAMP scores associated with the MPH exposure expected after the treatment with Ritalin LA at the dose of 40 mg were estimated using the model defined in Eqs. and the parameter values previously estimated …”

“…11 The PK/PD model previously developed to establish the exposure-response of MPH was used to estimate the changes in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) clinical scores associated with a single dose of 40 mg of Ritalin LA. 12 Finally, the optimization algorithm was applied to identify the dose and the in vivo/in Figure 1 General framework for maximizing the benefit-risk ratio of a treatment. PD, pharmacodynamic; PK, pharmacokinetic; IVIVC, in vitro/in vivo correlation.…”

“…The assessment of the exposure-response relationship was implemented using the PK/PD model previously developed describing the relationship of MPH concentrations (resulting from the administration of Concerta, Janssen-Cilag Manufacturing, LLC Gurabo, Puerto Rico 00778) with the SKAMP scores describing the ADHD impairment. 12 The placebo response evaluated with the SKAMP scores was described by an indirect response model (P(t)):…”

“…13-15 and the parameter values previously estimated. 12 Figure S3 shows the model-predicted MPH plasma concentrations and the associated model-predicted trajectories of the SKAMP scores for the three formulations. Simulations were conducted to estimate MPH exposure and SKAMP scores in the range of the recommended doses of Ritalin LA: 10 mg to 40 mg/day (Figure 6a).…”

“…Ritalin LA data extracted from the literature were used to implement an IVIVC . The PK/PD model previously developed to establish the exposure‐response of MPH was used to estimate the changes in Swanson, Kotkin, Agler, M‐Flynn, and Pelham scale (SKAMP) clinical scores associated with a single dose of 40 mg of Ritalin LA . Finally, the optimization algorithm was applied to identify the dose and the in vivo / in vitro release properties expected to maximize the benefit‐risk ratio of a treatment with MPH …”