Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Anuradha Ramamoorthy and Dr. Xinning Yang, Policy Leads in CDER’s Office of Clinical Pharmacology. They will be sharing some thoughts with us on the newly published final guidance titled Evaluation of Gastric pH-Dependent Drug Interactions with Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications. Welcome, Dr. Ramamoorthy and Dr. Yang! Thank you for speaking with us today.

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The first question is for Dr. Ramamoorthy. For listeners less familiar with this area, can you provide a little background on acid-reducing agents?

Sure, acid-reducing agents, or ARAs, are medications most commonly considered for the treatment of heartburn as well as some other gastrointestinal disorders. The ARAs work by reducing acid in the stomach. Many ARAs are available over-the-counter. ARAs include antacids, H2 blockers, and proton-pump inhibitors (or PPIs).

Why is it important to evaluate gastric pH change-dependent drug interactions involving ARAs?

Taking a drug concomitantly with an ARA can result in a gastric pH change-mediated drug-drug interaction. These are commonly referred to as pH-dependent DDI. As mentioned previously, ARAs reduce stomach acid levels, thereby leading to an increase in stomach pH. This change in pH can affect the systemic exposure of a concomitantly administered drug whose absorption is susceptible to pH changes. This could result in either a loss of efficacy or an increase in adverse events for some drugs. So, it is important to assess the susceptibility of an investigational drug to such DDI risk early in development to be able to characterize the DDI effect in clinical studies and communicate the relevant findings and mitigation options in the drug product labeling when needed.

Why is FDA issuing this guidance?

The other published DDI guidances focus on drug interactions that are mediated by a modulation of metabolic enzymes and drug transporters. As such, there is a need to address DDIs mediated by other mechanisms, such as change in gastric pH. FDA has been engaged in regulatory research to advance the knowledge around best practices for assessing pH-dependent DDIs for quite some time now, and the publication of this final guidance is a byproduct of those efforts.

Dr. Yang, when should an assessment of pH-dependent DDI potential be conducted during drug development?

We encourage drug developers to begin the assessment early in development. If the assessments indicate no risk of such DDIs, there will be no limitation of concomitant administration of ARA with the investigational drug. However, if the DDI risk cannot be ruled out, further assessment is needed, for example, by conducting stand-alone clinical DDI studies.

For some drugs, formulations change during the development process. It should be noted that the pH-dependent DDI effect can be formulation dependent. When the formulation used in late development is different from the formulation used in early development, a drug developer needs to reassess the DDI risk or provide a justification for why the DDI risk assessment for the early formulation can be applied to a later formulation.

What is a general framework for assessing clinical DDI risk with ARAs?

In the guidance, we have provided a flowchart that details a general framework for assessing pH-dependent DDI risk for immediate-release products. The evaluation of DDI liability of an investigational drug starts with the understanding of its physicochemical properties. Drug developers may compare drug solubility and dissolution profiles of the drug product measured in vitro under different pH conditions that mimic the pH of the stomach in the presence and absence of ARAs. This helps assess how likely a drug product is subject to pH-dependent DDI risk. If it is not likely, there is no need to continue testing the pH-dependent DDI risk in clinical studies. If DDI risk is likely or unknown, a clinical DDI study is usually recommended.

Alternative approaches may be considered, such as a population pharmacokinetic approach to analyze pharmacokinetic data from participants in clinical trials taking ARAs, or a physiologically based pharmacokinetic modeling method to simulate the DDI effect. Since this field is evolving, FDA encourages drug developers to speak with review divisions if they pursue a physiologically based pharmacokinetic modeling approach to evaluate pH-dependent DDIs.

What are some general considerations for designing clinical studies to evaluate pH-dependent DDI potential?

There is some nuance around this subject, with one important aspect being the selection of the ARA for clinical studies. The selection of ARAs and associated dosing regimens for dedicated clinical DDI studies depends on the purpose, for example, characterizing a worst-case scenario or identifying a mitigation strategy such as staggered administration. Among the currently approved ARAs, proton pump inhibitors, also called PPIs, are recommended for dedicated DDI studies, because their effects are long lasting when compared to other ARAs.

To characterize the worst-case scenario, we recommend that participants in DDI studies receive the highest dose of an ARA that is commonly used in clinical practice along with the highest dose of an investigational drug that is intended for therapeutic use.

To explore a mitigation strategy for a drug likely or known to interact with ARAs, staggered administration of H2 blockers or antacids relative to the dosing of a drug can be considered, since these ARAs affect stomach pH for a shorter duration compared to PPIs. In such studies, H2 blockers or antacids are administered at specified hours before and after the administration of an investigational drug.

Another consideration is whether a drug should be taken with or without food. If a drug is intended to be taken with food, the study should be conducted under fed conditions. If a drug can be taken regardless of food, the study should be conducted under fasted conditions since it represents the worst-case scenario.

How can data obtained with one ARA be applied to other ARAs?

In clinical studies to evaluate pH-dependent DDI potential, generally, the effects observed with an investigational drug and one ARA can be extrapolated to other ARAs within the same class. The guidance provides a framework to extrapolate results from a dedicated DDI study conducted with a PPI to other ARAs and offers considerations for additional clinical DDI studies. As mentioned earlier, PPIs generally represent a worst-case scenario due to their long-lasting effects on gastric pH. So, if we do not see clinically relevant pH-dependent DDI of a drug with a PPI, there is often no risk with other ARAs.

If there is a clinically significant pharmacokinetic change of a drug with a PPI, then we will often recommend that the medication not be taken with other PPIs or H2 blockers. Antacids can be taken two hours before or two hours after administration of a drug, because the antacids act locally and their effect on gastric pH is short. Drug developers can also conduct a clinical DDI study with an H2 blocker using a staggered administration approach, as described previously, to determine a mitigation strategy. Lastly, drug developers can also consider conducting a study with a lower dose of a PPI to see whether the lower dose shows no clinically significant effect on the investigational drug, and if so, the labeling could be updated to reflect the lower dose, where applicable, as a mitigation strategy.

Dr. Ramamoorthy, for our last question, what are a couple of key items that you especially want listeners to remember?

Since ARAs are available over-the-counter and are commonly used, it is important to appreciate the potential for a drug interaction when ARAs are concomitantly administered with other orally administered drugs. We encourage drug developers to assess pH-dependent DDI risk early in drug development. If no DDI risk is found, this will help avoid unnecessary restriction on concomitant medication use by patients in later clinical trials. If the risk cannot be ruled out, further characterization becomes necessary, for example, with clinical DDI studies, to better inform whether and how patients can take ARAs in clinical trials and inform instructions in drug labeling if approved. The eventual goal is to support Prescribing Information to ensure the safe and effective use of drugs by patients.

Dr. Ramamoorthy and Dr. Yang, thank you for taking the time to share your thoughts on the pH-dependent DDI final guidance. We all have learned so much from your experience and insights in this area, and we appreciate the hard work that you have invested to inform safe and effective use of the drugs and biologics we regulate. We would also like to thank the guidance working group for writing and publishing this guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.