EMA Issues Guideline on Potential Drug Interactions in the GI Tract
核心洞察
The European Medicines Agency (搜索) has issued a guideline on evaluating gastrointestinal drug interactions, covering extrinsic factors that can alter the absorption of orally administered medicines.
EMA recommends comparing bioavailability of a new active substance in the fasted state and after a high-fat meal to capture the most extreme exposure conditions.
The guideline also covers gastric pH changes, complex and chelate formation, excipients, gastric emptying and enterohepatic recirculation, including antibiotic effects on glucuronide metabolite recycling.
The European Medicines Agency (搜索) (EMA) has published a guideline on evaluating drug interactions in the gastrointestinal tract, addressing situations in which extrinsic factors in the GI tract may affect drug absorption. EMA noted that certain drug-drug interactions can cause adverse events or reduce or negate drug efficacy, and that an aging population relying on multiple medicines makes such issues more likely and potentially in need of interaction studies.
The guideline sets out how researchers should assess possible absorption interactions of new drugs. Factors to account for include changes in gastric pH, formation of complexes or chelates, and food effects, with possible consideration of formulation changes or how a drug is taken. EMA noted that food intake temporarily raises gastric pH, slows gastric emptying, increases luminal bile salts and enzymes, and increases intestinal and hepatic perfusion, all of which affect how much drug is absorbed and how quickly. It said these issues should be investigated as early as possible in development to estimate optimal dosage and to advise patients on appropriate foods in Phase 3 trials. Bioavailability of a new active substance should generally be compared in the fasted state and with a high-fat meal.
EMA also discussed gastric pH effects on drug-drug interactions, gastric emptying and intestinal motility, noting that some drugs and excipients alter gastric emptying and thereby absorption, which matters especially for drugs with a narrow therapeutic window or early onset of clinical action. The guideline includes recommendations on excipients such as diluents, fillers, binders, lubricants, coatings, solvents, flavoring agents and dyes, and on complex formation and enterohepatic recirculation. EMA cited bile acid sequestrants, which can decrease absorption of drugs undergoing hepatic recirculation through complex formation or reduced solubility, and oral antibiotics that interfere with enterohepatic recirculation of drugs excreted in bile as glucuronide metabolites by killing the intestinal bacteria whose beta-glucuronidase enzymes convert those metabolites back to parent drug. The guideline also addresses reporting and interpretation of data from these studies and risk assessment.