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Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about the evaluation of gastric pH-dependent drug interactions with acid-reducing 

agents, read the guidance.

Evaluation of Gastric pH-Dependent Drug 

Interactions With Acid-Reducing Agents: Study 

Design, Data Analysis, and Clinical Implications

Final Guidance for Industry

What is recommended 

in this guidance?

This final guidance provides current FDA 

recommendations on evaluating pH-dependent 

drug-drug interactions (DDIs) during drug 

development, including: 

• When clinical studies are needed to assess 

pH-dependent DDIs

• Design and interpretation of clinical DDI 

studies to assess pH-dependent DDIs

• Management of pH-dependent DDIs via 

labeling recommendations

Why is this 

guidance important?

A DDI can occur when two or more drugs are 

co-administered. Acid-Reducing Agents (ARAs) 

are widely used drugs that can treat a number of 

disorders, including heartburn. ARAs can elevate 

gastric pH, which could alter the bioavailability 

of concomitantly administered drugs, potentially 

resulting in loss of efficacy or increased toxicity.

What are Acid-Reducing 

Agents (ARAs)?

ARAs are among the most commonly 

used drugs in the U.S.

Common ARAs include antacids, 

histamine H2-receptor antagonists 

(H2 blockers), and proton pump 

inhibitors (PPIs)

 Many ARAs are available over 

the counter

 ARAs work by reducing acid in the 

stomach and are used for a number 

of disorders, including heartburn

Guidance Snapshot for Industry
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Guidance Recap Podcast

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Guidance Snapshots are a communication tool and are not a substitute for the guidance document.

To learn more about the evaluation of gastric pH-dependent drug interactions with acid-reducing 

agents, read the guidance. 

To see additional Guidance Snapshots, check out the pilot program. 2

Speaker(s): Xinning Yang, PhD, and Anuradha Ramamoorthy, PhD

Drug Development Timeline

* Apply the Guidance Recommendations Early in Drug Development

Assessment of pH-Dependent DDI Potential

Why: 

Drug developers should 

assess the potential 

for pH-dependent DDIs 

during development of an 

investigational new drug 

because ARAs are among 

the most commonly used 

drugs in the U.S. and 

pH-dependent DDIs can 

result in a loss of efficacy 

or increased toxicity 

for concomitantly 

administered drugs.

When: 

It is important to assess 

the susceptibility of 

investigational drugs 

to DDIs mediated by 

changes in gastric pH 

early in drug development.

How:

This guidance describes 

approaches for:

Assessment of DDI risk 

with an ARA based on the 

physicochemical properties 

of the investigational drug 

substance and dissolution 

profiles of the drug product

Characterization of DDI 

effects, including clinical 

investigations 

when appropriate

Communication of 

relevant findings in drug 

product labeling

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

FDA 

FILING & 

APPROVAL

PRECLINICAL 

DEVELOPMENT*

Sponsors should perform

an assessment of DDI risk

with an ARA based on the

physicochemical properties

of the investigational drug.

POSTMARKET OR 

POSTAPPROVAL 

STUDIES

CLINICAL 

DEVELOPMENT*

In general, if a drug is

determined to have the

potential for a pH-dependent

DDI, the sponsor should

conduct a clinical study to

characterize the effect of ARAs

on the pharmacokinetics of the

investigational drug or provide

a rationale justifying the lack

of a pH-dependent DDI based

on in vitro, in silico, or

clinical information.