Purpose: Methylphenidate Hydrochloride (Concerta®) is approved as a multiphasic modified-release formulation, designed to achieve both rapid onset of activity and sustained activity with a duration of 12 hours. FDA guidance for Methylphenidate Hydrochloride recommends that partial area under the curve (pAUC) metrics are calculate in addition to the traditional (AUC0-∞ and Cmax) metrics to ensure that a generic formulation (test) is therapeutically equivalent to Concerta® (reference). These additional pAUC metrics are intended to better characterize systemic exposure responsible for the early onset of response, for sustaining the response in the middle of the once-daily dosing interval, and for maintenance of the response in late stage of the once-daily dosing interval. To ensure the switchability between Concerta® and generic products, the guidance requires to establish average bioequivalence by calculating 90% confidence intervals of the geometric mean test/reference (T/R) ratios for the pAUCs, Cmax and AUC0-∞, and showing that they fall within the limits of 80-125%. In addition, a subject-by-formulation test for each PK metric is recommended. Phoenix® WinNonlin templates can be used to guarantee standardization and accuracy of the calculations and statistical analysis needed to show bioequivalence for generic products and Concerta®.
Methods: Phoenix templates in general provide a means of creating a collection of data-processing and computational tools that can be reused with different datasets. Phoenix templates specific to meet the recommendations outlined in the FDA guidance on Methylphenidate Hydrochloride were developed. The templates require some initial input by the user but automate the calculation of the additional partial AUC parameters and perform the appropriate statistical analysis to test bioequivalence as specified by the FDA guidance. The guidance also recommends different pAUC time intervals for fasted versus fed studies, and the Phoenix templates can handle both types of studies. The parts of the template that do not require user input are locked to guarantee the consistency of the automated calculations.
Results: A dataset for a new formulation of Methylphenidate Hydrocholride was modified to remove proprietary information and different levels of noise were added to generate three different tests datasets. Bioequivalence analyses were performed using Phoenix templates to compare the three datasets to the reference. Bioequivalence results obtained with Phoenix templates matched results using SAS code.
Conclusion: Although numerous steps were required, Phoenix WinNonlin has the capability to perform bioequivalence calculations according to the FDA guidance for Methylphenidate Hydrochloride using Phoenix templates that require very minimal input by the user. Phoenix templates can be easily reused with different datasets. The Phoenix templates and example projects presented in this poster are available for download at Certara University.