PII-013 - EVALUATING DRUG-DRUG INTERACTIONS WITH ACID-REDUCDING AGENTS: INSIGHTS FROM FDA GUIDANCE AND RECENT APPROVALS

M. Le¹, J. Oldenhof²; ¹Biopharma Services, non-US, Canada, ²University of Toronto, non-US, Canada.

Background: Proton-pump-inhibitor drugs (PPI) are among the most widely used acid-reducing agents (ARA), with many available over the counter. Administration of ARA/PPI increases intragastric pH and alters gastric hydrogen ion concentration, which can affect the solubility, dissolution, and bioavailability of concomitant medications, potentially altering efficacy and/or toxicity. It is important to note that, PPI can also interact with other mechanisms.
In March 2023, FDA issued the new guidance, entitled “Evaluation of Gastric pH-Dependent Drug Interactions with Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications”, outlining the necessity for investigating and conducting drug-drug interaction (DDI) studies with ARAs early in drug development and address these findings in the product labeling as needed.
This poster provides an overview of the FDA approval packages for gastric pH-dependence drugs and reviews various approaches to evaluating their interaction with ARAs.

Methods: The approval packages from Center for Drug Evaluation and Research (CDER) for all newly approved oral drugs in 2021, 2023, and 2024 were reviewed to evaluate the DDI between drugs and PPI/ARAs.

Results: CDER approved a total of 134 new drugs in 2021, 2023, and 2024 (up to 19 Aug 2024), of which 56 drugs are for oral administration. Interactions with ARA were discussed in 28 drug assessments, with DDI studies being the most common approach to assess the impact of ARA/PPI. Besides seeking a waiver for DDI studies based on dissolution studies in varying pH conditions, some innovators performed retrospective studies or established population pharmacokinetic (popPK) models by pooling data from phase 2 and 3 studies to support label claims. In rare instances where PK modeling was insufficient or interaction risks were not addressed during the drug development, conditional approvals could be granted, requiring continued post-marketing evaluation of ARA interaction.

Conclusion: Addressing the drug interactions with ARA is crucial for gastric pH-dependence drugs and should be integrated into the oral drug development plan. The FDA guidance offers a framework for both clinical studies and alternative non-trial methods to assess these drug interactions.