The European Medicines Agency (EMA) has published a draft Guideline on the investigation of interactions in the gastrointestinal tract, introducing a dedicated framework for assessing drug interactions that can alter gastrointestinal absorption.
The draft was adopted by the Committee for Medicinal Products for Human Use (CHMP) on June 15, 2026, with the public consultation running from September 11 to December 31, 2026. For pharmaceutical companies developing orally administered medicines, the document provides important considerations for clinical pharmacology, formulation development and regulatory strategy.
The guideline is particularly relevant in the context of the current European drug-interaction framework. ICH M12, which formally superseded the previous EMA guideline on drug interactions in November 2024, focuses primarily on pharmacokinetic interactions mediated by metabolic enzymes and transporters. GI-mediated absorption interactions are not covered to the same extent. The new EMA guideline is intended to address this specific area.
Why gastrointestinal interactions matter
Drug interactions do not necessarily require systemic metabolic or transporter mechanisms. Changes occurring directly within the gastrointestinal tract can modify the rate or extent of drug absorption and consequently affect clinical exposure, efficacy or safety.
The EMA draft identifies several potential mechanisms, including food intake, changes in gastric pH, gastric emptying and intestinal motility, excipients, complex formation and enterohepatic recirculation. The scope also extends to certain formulation changes and alternative methods of administration.
This broad scope is particularly relevant for products whose absorption is sensitive to physicochemical or physiological conditions. It also reinforces the need to consider GI interactions as part of an integrated development strategy rather than as an issue addressed only late in clinical development.
Food-effect studies: an early development consideration
One of the clearest messages from the draft guideline is that food effects should be investigated early.
Food can modify gastric pH, gastric emptying, luminal bile salts and enzymes, as well as intestinal and hepatic perfusion. These physiological changes may alter both the rate and extent of absorption.
EMA generally recommends comparing exposure under fasted conditions with exposure following a high-fat meal, considered the most extreme situation for assessing a potential food effect. Where a clinically relevant effect is identified, additional studies may be needed to establish whether the interaction depends on the type of food or the timing of administration.
From a regulatory perspective, an important point is that the food-effect assessment should not be considered independently of the final product. If formulation changes are introduced during development, the food effect of the commercial formulation should also be addressed, either through a dedicated study or an adequate scientific justification.
Gastric pH: a key area for clinical pharmacology
The draft guideline gives considerable attention to interactions caused by acid-reducing agents (ARAs), including proton pump inhibitors (PPIs), H2 antagonists and antacids.
The highest concern is generally associated with weak bases having low intrinsic aqueous solubility. Increasing gastric pH can reduce their solubility and consequently their absorption, potentially resulting in reduced efficacy. Where in vitro data indicate that pH-dependent solubility may affect absorption, EMA generally recommends an in vivo interaction study with an appropriate ARA.
The study design should reflect the regulatory question being addressed. A worst-case study should expose the investigational medicine to the maximum effect of the ARA, whereas staggered administration can be investigated when the objective is to identify a practical strategy for avoiding the interaction.
PPIs are particularly important because their effect on gastric pH is prolonged. EMA recommends administration for at least four days in an interaction study to reach pharmacodynamic steady state. Selection of the PPI, dose and timing should be justified. Potential CYP2C19 inhibition should also be considered where relevant.
Beyond pH: formulation, excipients and GI motility
The draft guideline expands the interaction assessment beyond traditional food and pH considerations.
Medicines such as opioids and GLP-1 receptor agonists, as well as certain excipients, can affect gastric emptying or intestinal motility. This may be particularly relevant for medicines with a narrow therapeutic window, rapid-onset requirements, modified-release characteristics or limited absorption windows.
Excipients are also explicitly brought into the interaction assessment. Substances commonly regarded as pharmacologically inactive may influence solubility, dissolution, intestinal permeability, transporters or GI motility. The potential impact of an excipient on a concomitantly administered medicine should therefore be assessed mechanistically, considering its amount, mechanism of action and the absorption characteristics of the interacting drug.
This has potential implications for both pharmaceutical development and lifecycle management, particularly where formulation composition changes during development.
Complexation and enterohepatic recirculation
The EMA draft also addresses physicochemical interactions that can reduce drug absorption.
Multivalent cations, including calcium, magnesium, aluminium and iron, may form complexes with orally administered medicines. Similar considerations apply to polymeric phosphate binders such as sevelamer and lanthanum carbonate. Where physicochemical and in vitro data indicate a potential interaction, an in vivo study may be required, potentially supporting a recommendation to separate administration times.
Enterohepatic recirculation represents another mechanism requiring case-by-case consideration. Bile acid sequestrants may reduce absorption, while some oral antibiotics may disrupt the intestinal bacterial processes required for reactivation and reabsorption of glucuronidated metabolites.
From interaction data to SmPC recommendations
A key regulatory feature of the draft is its emphasis on translating pharmacokinetic findings into clinically meaningful risk management.
For food and drug interaction studies, EMA recommends reporting AUC₀–t, Cmax and Tmax, together with geometric mean ratios and 90% confidence intervals. Individual variability should also be characterised, and pharmacodynamic endpoints should be reported where available. Importantly, results should be interpreted in relation to the therapeutic window of the medicinal product rather than solely on the magnitude of the pharmacokinetic change.
Where a clinically relevant interaction is identified, potential management strategies include contraindication or avoidance of concomitant treatment, dose modification, temporary treatment interruption, staggered administration, substitution with an alternative medicine, or specific monitoring strategies such as therapeutic drug monitoring.
Any proposed risk-minimisation measures or alternative strategies should be reflected in the Summary of Product Characteristics (SmPC), as appropriate.
What should sponsors consider now?
For sponsors developing new medicines, the draft guideline provides a useful framework for integrating GI interaction assessment into the overall development programme.
Key considerations include:
- identifying potential GI-mediated interactions from physicochemical and formulation data early in development;
- evaluating food effects before pivotal clinical development;
- assessing pH-dependent solubility and the potential relevance of acid-reducing agents;
- considering the impact of formulation changes and excipients;
- assessing the potential consequences of altered gastric emptying or intestinal motility;
- investigating complex formation where supported by mechanistic and in vitro evidence; and
- translating clinically relevant findings into clear dosing and risk-minimisation recommendations.
Regulatory impact
The draft guideline represents an important complement to ICH M12 and provides a more structured European framework for interactions occurring within the GI tract.
For regulatory and clinical development teams, its significance extends beyond the conduct of individual DDI studies. The document encourages an integrated, mechanism-based assessment linking in vitro evidence, clinical pharmacokinetics, therapeutic exposure, formulation characteristics and risk management.
As the public consultation continues until December 31 2026, sponsors should consider reviewing ongoing development programmes against the proposed recommendations and assessing whether existing interaction strategies adequately address the GI-mediated mechanisms described by EMA.
