FDA Announces Availability of a Public Docket, “Framework for Assessing pH-Dependent Drug-Drug Interactions”
On May 22, 2018, the U.S. Food and Drug Administration (FDA) announced the availability of a public docket entitled “Framework for Assessing pH-Dependent Drug-Drug Interactions” to assist with the development of a policy or guidance document on the assessment of pH-dependent drug-drug interactions (DDIs).
Acid-reducing agents (ARAs) such as antacids, histamine H2-receptor antagonists (H2 blockers), and proton pump inhibitors (PPIs) are widely used, and many of these products are available over the counter. For a drug whose solubility is pH-dependent, concomitant administration with an ARA may affect its absorption and systemic exposure, potentially resulting in loss of efficacy or, in some cases, increased toxicity. Therefore, it is important to assess a drug’s susceptibility to pH-dependent DDIs during drug development, characterize the DDI effect with clinical studies when needed, and communicate study results in the drug labeling.
In October 2017, FDA published two draft guidance documents on DDIs entitled “In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies” (In Vitro Studies Draft Guidance) and “Clinical Drug Interaction Studies--Study Design, Data Analysis, and Clinical Implications” (Clinical Drug Interaction Studies Draft Guidance). These two draft guidances focus on enzyme- and transporter-based DDIs and do not include a framework to assess pH-dependent DDIs.
Interested persons are invited to provide detailed information and comments on approaches to assess pH-dependent DDIs. FDA is particularly interested in responses to the following overarching questions and will consider all information and comments submitted in a timely manner:
- What are the characteristics of drugs that are susceptible to pH-dependent DDIs? Can a stepwise approach be applied to evaluate the interaction potential? Please provide the rationale for your suggestions.
- When conducting pH-dependent DDI assessments:
a. What are the utilities and limitations of different approaches to evaluating DDIs
(e.g., in silico, in vitro, and dedicated clinical studies, as well as population
b. What are the study design considerations (e.g., study population, choice of ARAs,
dosing regimen and administration, and pharmacokinetic sampling) for the in vivo
assessments discussed in 2a above? Please describe the rationale for any design
c. Can we extrapolate the findings from a clinical DDI study with one ARA drug
(a PPI, H2 blocker, or antacid) to anticipate the DDI potential for other ARAs in the
same class or in a different class? Please provide the rationale for your proposal.
The Framework for Assessing pH-Dependent Drug-Drug Interactions public docket is available athttps://go.usa.gov/xQmrq. Please refer to the public docket for more details.
FDA established this public docket to collect public comments. You may submit your comments to this public docket by July 23, 2018 to the Docket No. FDA-2018-N-1820 available athttps://www.regulations.gov. Your comments do make a difference and can impact the outcomes of FDA regulatory policy. Share your knowledge and experience, and make your voice count