Leveraging Model Integrated Bioequivalence (MIBE) to Address Regulatory Concerns and Waive Repeat Bioequivalence...

In recent years, model-informed strategies such as the model integrated bioequivalence (MIBE) approach have gained significance due to their ability to enable decision making, streamline drug product development, and to waive bioequivalence studies, as applicable. In this work, we demonstrate the successful application of the MIBE approach that led to the waiver of a repeat fasting and fed bioequivalence studies for clopidogrel bisulfate 300 mg tablets. In the pivotal bioequivalence study, pharmacokinetic sampling in fasting and fed conditions was performed until 12 h, shorter than the recommended sampling up to at least three half-lives of the drug. The mean half-life of reference listed drug clopidogrel was 6 h. During dossier review, a query was received from the regulatory agency to assess the impact of early termination of the study on AUC_0-inf and bioequivalence assessment, although the pivotal study demonstrated average bioequivalence. To address this, a population pharmacokinetic model was developed under fasting and fed conditions based on the pilot study data that included data until 24 h. Further, the pivotal study pharmacokinetic parameters were predicted based on a model developed with pilot data and complete profiles until 10 half-lives were simulated. The model-derived parameters were utilized to assess preserving Type-1 error rate at 5% and bioequivalence was simulated. The simulations demonstrated average bioequivalence under fasting and fed conditions, and the 90% confidence intervals within 80%-125%. Overall, the MIBE approach demonstrated that truncated sampling till 12 h did not compromise the interpretability of pivotal study, thereby alleviating the need for a repeat bioequivalence study.