Drugs

Guide on Gastric pH-Dependent Drug Interactions

FDA has released a final guidance entitled “Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications.” Acid reducing agents (ARA) can increase gastric pH which may affect the solubility and dissolution characteristics of some orally administered drugs, the agency says. “As a result, concomitant administration of a drug with an ARA could alter the bioavailability of the drug, potentially resulting in a loss of efficacy for weak-base drugs or increased adverse events for weak-acid drugs,” it says.

Common ARAs such as antacids, histamine H2-receptor antagonists, and proton pump inhibitors are widely used, and this presents a “potential risk for clinically significant drug-drug interactions (DDIs) with concomitant administration of drugs with ARAs,” the guidance says. “Therefore, it is important to assess the susceptibility of an investigational drug to DDIs mediated by gastric-pH changes (referred to as pH-dependent DDIs) early in drug development, characterize the DDI effect with clinical studies when needed, and communicate the relevant findings and mitigation options where available in the drug product labeling.”

The document describes the agency’s recommendations on: (1) when clinical DDI studies with ARAs are needed; (2) the design of such clinical DDI studies; (3) how to interpret these study results; and (4) communicating these findings in drug product labeling.

According to the guidance, sponsors should evaluate any potential of pH-dependent DDIs for a drug during early development so dosing of the drug with ARAs in subsequent clinical trials can be understood, especially for indications where a significant proportion of patients are likely to be taking ARAs. “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,” it says.

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