EMA guideline addresses concerns with potential drug interactions in the GI tract
The European Medicines Agency (EMA) has published a guideline on evaluating drug interactions in the gastrointestinal tract that addresses situations in which extrinsic factors in the gastrointestinal tract may affect drug absorption.
EMA noted that certain drug-drug interactions may cause adverse events or reduce or negate the efficacy of the drugs. The agency added that with an aging population that is more prone to relying on multiple drugs, such issues are more likely to occur and may require interaction studies.
"The aim of interaction studies performed on new medicinal products is to gain knowledge of how the new medicinal product affects the safety and efficacy of other medicinal products and vice versa," said EMA. "Interactions in the upper gastrointestinal tract can result from extrinsic factors affecting the absorption of orally administered medicinal products.
"In addition to gastric pH changes, food intake, product formulation and formation of complexes or chelates can affect the intestinal absorption of a drug and this may have consequences for efficacy or safety," the agency added.
The guideline recommends how researchers should evaluate the possible absorption interactions of new drugs, specifically in the gastrointestinal tract. Such interactions may need to account for changes in gastric pH, the formation of complexes or chelates, and the effects of foods, and may take into consideration changes in formulations or how the drug is taken.
EMA notes that food intake temporarily changes the physiological conditions of the gastrointestinal tract by increasing gastric pH, slowing gastric emptying, increasing luminal bile salts and enzymes, and increasing intestinal and hepatic perfusion, all of which affect how much drug is absorbed and how quickly. The agency said such issues should be investigated as early as possible in the drug development process to enable researchers to estimate the optimal drug dosage and to ensure patients are advised on the right foods in Phase 3 clinical trials.
"In general, intake of a medicinal product in relation to meal times should aim at minimising variability of exposure and obtaining safe and efficacious exposure, without causing unnecessary restrictions for the patient," said EMA. "Another common reason for recommending intake with food is gastrointestinal tolerability issues.
"In general, the bioavailability of the active substance of a new medicinal product should be compared under the most extreme situations i.e., in fasted state and with a high-fat meal," the agency added.
In addition to evaluating food effects, EMA discussed the need to investigate the effects of gastric pH on drug-drug interactions and on gastric emptying or intestinal motility. The agency noted that certain drugs and excipients are known to cause gastric emptying, or how food moves through the digestive system, which ultimately affects their absorption. Studying this effect is especially important for drugs with a narrow therapeutic window or an early onset of clinical action.
The guideline also includes considerations and recommendations for evaluating excipients, such as diluents, fillers, binders, lubricants, coatings, solvents, flavoring agents, and dyes, as well as complex formation and enterohepatic recirculation. The agency noted that the bioavailability of drugs that undergo enterohepatic recirculation may be affected in certain situations, potentially reducing their effectiveness.
"For example, bile acid sequestrants can decrease the absorption of drugs that undergo hepatic recirculation by mechanisms such as complex formation or decreased solubility," said EMA. "Additionally, several oral antibiotics may interfere with the enterohepatic recirculation of drugs excreted in the bile as glucuronide-metabolites.
"These metabolites are further deglucuronidated by β-glucuronidase enzymes present in intestinal bacteria allowing the parent drug to be reabsorbed into the circulation," the agency added. "Antibiotics, which kill those bacteria, prevent the glucuronide-metabolite to be converted back to the parent drug, and in this way lower the bioavailability of the parent drug."
Additionally, the guideline addresses how to report and interpret data from studies evaluating drug interactions in the gastrointestinal tract and assess risk in such studies.
