Novel application of PBBM to justify impact of faster dissolution on safety and pharmacokinetics – a case study and utility in regulatory justifications

Physiologically based biopharmaceutics modelling (PBBM) was recognised as potential approach for biopharmaceutics applications. However, PBBM to justify safety is an unexplored area.In this manuscript, we elucidated PBBM application for safety justification. Product DRL is a generic extended release tablet containing an anti-epileptic narrow therapeutic index (NTI) drug. During dossier review, regulatory agency requested to evaluate the impact of faster dissolution profiles observed during stability on safety aspects. In order to justify, PBBMbased strategy was adapted.Model was validated and population simulations were performed for reference and test formulations and the predictions matched with clinical outcome. The model was found to be sensitive to dissolution changes and hence applied for the prediction of stability batches exhibiting faster dissolution profiles, virtually generated profiles at lower and upper specifications. The maximum predicted plasma levels were well below the reported safety levels, thereby demonstrating safety of the product.Overall, a novel application of PBBM to justify safety was demonstrated. Similar justifications using PBBM and linking with safety can be adopted where safety can be impacted due to aggravated dissolution profiles. Such justifications have potential to avoid clinical safety studies and helps in faster approval of drug product.