The EMA’s draft guideline extends ICH M12 drug interaction studies to the gut. See what it asks on food effect, gastric pH, and excipients, and how to respond.
The European Medicines Agency (EMA) has opened consultation on a draft guideline that covers the gut interactions left out of ICH M12 drug interaction studies.
It addresses food effects, gastric pH, motility, excipients, and chelation. Comments close on 31 December 2026.
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What Drug-Drug Interactions Are and Why They Matter
A drug-drug interaction (DDI) occurs when one medicine changes how another behaves in the body. Exposure may rise and cause side effects.
On the other hand, exposure may also fall and weaken the treatment effect.
Pharmacokinetic interactions change what the body does to a drug. They affect absorption, distribution, metabolism, or excretion (ADME).
And, finally, but not least, pharmacodynamic interactions change what a drug does to the body, for example when two medicines add to each other's effect.
Regulators have focused mostly on metabolism and transport.
Enzymes such as the cytochrome P450 family break drugs down for metabolism.
Transporter proteins move drugs across membranes. One drug can block or boost these systems and shift the exposure of another.
Polypharmacy raises the stakes
The EMA points out that an ageing European population takes more medicines, which makes interactions more likely.
Sponsors must therefore test interaction risk before approval and write the findings into product labelling.
Gut interactions differ from metabolic ones in one respect. They last only while both drugs share the gastrointestinal tract. Timing changes, such as staggered dosing, can therefore reduce many of them.
Where interactions happen in the body
Gut: Food, gastric pH, motility, excipients, and chelation change how much drug enters the blood.
Liver and gut wall: Enzymes and transporters change how fast a drug is cleared.
Bile and kidney: Transport and recirculation change how a drug leaves the body.
Target tissue: Pharmacodynamic effects add to, oppose, or amplify one another.
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Why ICH M12 Drug Interaction Studies Left a Gap
The International Council for Harmonisation (ICH) finalised its M12 guideline on 21 May 2024, and the draft attracted over 1,000 comments from 20 companies.
The industry wanted clearer study timing and scope. Regional differences had also raised development costs and delayed patient access.
The text covers enzyme- and transporter-mediated pharmacokinetic interactions, mainly for small molecules.
The European Union brought ICH M12 into effect on 30 November 2024, and it replaced the EMA’s earlier interaction guideline.
The U.S. Food and Drug Administration (FDA) adopted the guideline in August 2024. It replaced the agency’s 2020 in vitro and clinical guidances.
Drug developers now work from one core rulebook for enzyme and transporter studies.
The old EMA guideline also covered interactions in the upper gut, while ICH M12 does not represent them to the same extent.
The EMA answered with a concept paper in May 2025, and the Committee for Medicinal Products for Human Use (CHMP) adopted the resulting draft for consultation on 15 June 2026.
What the gap means for development strategy
The draft turns absorption questions into planned studies.
It asks sponsors to test food effect early, so dose finding and phase 3 meal advice rest on data.
If this is not done and documented early on, late surprises can force protocol amendments and repeat studies.
Formulation changes carry weight too. A switch between clinical and commercial formulations reopens the food effect question.
Sponsors must run a study or justify a similar effect from solubility, bioavailability, and the nature of the change.
Co-medications add another pressure. As a result, the draft names GLP-1 receptor agonists among drugs that alter gastric emptying, even when given by injection.
Oral drugs with narrow therapeutic windows or fast-onset benefits deserve early questions about such partners.
Alignment remains the open question.
ICH M12 united enzyme and transporter rules across regions, yet gut interactions still sit in regional texts.
Industry comments can push for convergence with the FDA approach, or show where the EU asks for more.
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Inside the Draft Guideline: Six Interaction Areas
The draft, coded EMA/136069/2026, applies mainly to oral, systemically acting drugs.
Locally acting gut products can borrow many recommendations.
The standard test compares fasted dosing with a high-fat meal of 800 to 1,000 kcal. If that meal has no clinically relevant effect, the draft guideline says other meals generally will not matter either.
The standard crossover study gives a single dose with 150 to 250 ml of water after a 10-hour fast. Dosing follows either no meal or a meal that started 30 minutes earlier. Subjects then avoid food for at least four hours, and intake stays standardised for 12 hours.
A therapeutic dose usually serves. Drugs with non-linear pharmacokinetics may need the highest and lowest doses. While this is true for less-than-dose-proportional increases, for larger-than-proportional increases, the highest dose is generally sufficient.
Crushing a tablet, opening a capsule, or using a feeding tube also needs support, and the draft generally expects an in vivo relative bioavailability study unless justified. A justification can rest on Biopharmaceutics Classification System class, dissolution rate, existing bioequivalence data, and/or the therapeutic window.
Gastric pH and acid-reducing agents
Drugs with strongly pH-dependent solubility generally warrant an in vivo study with an acid-reducing agent (ARA).
Weak bases with low intrinsic solubility carry the highest risk. A higher gastric pH can cut their absorption and efficacy. Weak acids need a decision based on the safety profile.
Here, study aim drives design.
A worst-case study doses the ARA and the drug when ARA effects peak. A study that supports alternative dosing staggers the two.
The ARA should run at the highest recommended dose, long enough to reach its full effect.
Prandial state matters too.
Drugs taken with food need testing under fed conditions with a moderate-fat meal of about 400 to 500 kcal. Drugs taken regardless of food need fasted testing, because fasting is the worst case for absorption.
Additionally, H2 antagonists act quickly and last about 12 hours, so a single-dose crossover study usually works. Antacids act fast but briefly, so timing needs care, and their salts may bind the drug.
Proton pump inhibitors (PPIs) serve as the worst-case test.
Sponsors should dose the PPI for at least four days. A clean PPI result lets sponsors extrapolate to H2 antagonists and antacids. A positive result calls for follow-up studies with staggered dosing.
The FDA already issued its own gastric pH guidance in March 2023. Global teams should compare the two texts early and flag any differences in study design.
Motility, excipients, and other mechanisms
Gastric emptying and motility: Opioids and GLP-1 receptor agonists can change the absorption of other drugs, and paracetamol can serve as a probe substrate.
Excipients: Solubilisers and sugar alcohols such as mannitol and sorbitol may alter absorption of co-administered drugs, and absorption enhancers need comparative studies.
Complex formation: Multivalent cations, mineral supplements, and phosphate binders can reduce absorption, and a time gap may solve the problem.
Enterohepatic recirculation: Bile acid sequestrants and some antibiotics can lower the bioavailability of recirculating drugs.
For common excipients, literature data usually suffice to inform the Summary of Product Characteristics (SmPC). An in vivo study becomes necessary when the risk cannot be estimated any other way.
Reporting, modelling, and risk management
Sponsors should report geometric mean ratios with 90% confidence intervals for area under the curve up to the last quantifiable time-point (AUC0-t), maximum plasma concentration (Cmax), and time to maximum plasma concentration (tmax).
They should also show individual variability and judge results against the therapeutic window. Food advice given for tolerability reasons belongs in SmPC section 4.2.
Population pharmacokinetic analysis can add evidence when ARA use is well documented, but ARA classes should not be pooled. Physiologically based models may help when qualified for the context of use, with reference to ICH M15.
Risk management options range from contraindication to staggered dosing and monitoring. Staggering often works for gut interactions. Long-acting PPIs usually rule it out.
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What Sponsors Should Do Before the 31 December Deadline
In short, the new EMA draft closes a gap that ICH M12 drug interaction studies leave open.
It gives the EU one reference for food, pH, motility, excipient, chelation, and recirculation risks.
It also invites industry to shape the final text. Any risk minimisation measure then belongs in the SmPC.
For pharma teams, they should look to:
Audit pipeline assets for weak-base solubility, pH-dependent release, and food effect plans.
Map current evidence against the PPI-first strategy and fasted-state design.
Compare with FDA guidance and record differences for global development plans.
Review formulation changes, alternative administration routes, and excipient roles.
Submit comments through the EUSurvey form before the deadline.
Teams in Clinical Development should also link interaction planning to protocol design. Pharmatica’s Insights into the September 2026 MHRA GCP inspection update shows how quickly regulatory expectations move.
The draft may change after consultation, so early mapping speeds any response.
At Pharmatica, we translate regulatory shifts like this into clear strategic Insights, connecting guidelines, evidence, and market dynamics so decision-makers can act with confidence when it matters most.
Pharmatica: Insight. Connection. Impact.
Frequently Asked Questions
What is a drug-drug interaction?
A drug-drug interaction occurs when one medicine changes the absorption, metabolism, distribution, excretion, or effect of another. The result can be higher toxicity or lower efficacy. Developers study these risks before approval.
What is ICH M12?
ICH M12 is a harmonised guideline on drug interaction studies. It covers enzyme- and transporter-mediated interactions, mainly for small molecules. The EU applied it from 30 November 2024.
What does the EMA draft guideline on gastrointestinal interactions cover?
It covers food effects, gastric pH interactions with acid-reducing agents, gastric emptying, excipients, complex formation, and enterohepatic recirculation. It also sets reporting and risk management expectations.
Why does gastric pH affect drug absorption?
Some drugs dissolve well only within certain pH ranges. Acid-reducing agents raise gastric pH, so weak bases with low solubility dissolve less. Less dissolved drug means less absorption and possibly weaker efficacy.
When does the consultation on the draft guideline close?
The consultation runs from 11 September to 31 December 2026. Stakeholders submit comments through the EMA's EUSurvey form.
Nicole (BSc Molecular Medicine, Honours Medical Biochemistry) has many years of pharmaceutical experience, having worked for top CROs and biopharma companies for more than a decade.
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