FDA Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents Study Design, Data Analysis, and Clinical Implications

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Draft — Not for Implementation 1 Evaluation of Gastric pH-Dependent Drug Interactions With Acid-

2 Reducing Agents: Study Design, Data Analysis, and Clinical 3 Implications 1

4 Guidance for Industry 5 6 7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 11 for this guidance as listed on the title page. 12 13 14 15 16 I. INTRODUCTION 17 18 Elevation of gastric pH by acid-reducing agents (ARAs) can affect the solubility and dissolution 19 characteristics of orally administered drug products. As a result, concomitant administration of a 20 drug with an ARA could alter the bioavailability of the drug, potentially resulting in a loss of 21 efficacy for weak-base drugs or increased adverse events for weak-acid drugs. ARAs such as 22 antacids, histamine H -receptor antagonists (H blockers), and proton pump inhibitors (PPIs) are 2 2

2, 3 23 widely used, and many of these drugs are available over the counter. Consequently, there is an 24 increased risk for clinically significant drug-drug interactions (DDIs) with concomitant 25 administration of drugs with ARAs. Therefore, it is important to assess the susceptibility of an 26 investigational drug to DDIs mediated by gastric-pH changes (referred to as pH-dependent 27 DDIs) early in drug development, characterize the DDI effect with clinical studies when needed, 28 and communicate the relevant findings in the drug product labeling. 29 30 This guidance describes the FDA’s recommendations regarding: (1) when clinical DDI studies 31 with ARAs are needed; (2) the design of clinical DDI studies; (3) how to interpret study results; 4

32 and (4) communicating findings in drug product labeling. 33 1

This guidance has been prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, in the Center for Drug Evaluation and Research at the Food and Drug Administration. 2

Centers for Disease Control and Prevention's (CDC's) National Health and Nutrition Examination Survey, available at: https://www.cdc.gov/nchs/data/hus/hus16.pdf#079 (accessed May 16, 2018). 3

Zhang L, F Wu, SC Lee, H Zhao, and L Zhang, 2014, pH-Dependent Drug-Drug Interactions for Weak Base Drugs: Potential Implications for New Drug Development, Clin Pharmacol Ther, 96(2):266-277. 4

For general considerations regarding the evaluation of DDIs during drug development, see FDA’s guidance for industry Clinical Drug Interaction Studies – Cytochrome P450 Enzymes and Transporters-Mediated Drug Interactions (January 2020). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 1

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