Motility-mediated drug interactions with GLP-1 receptor agonists: labeled evidence and a framework for quantitative assessment

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, and two additional oral products received US approval in 2025 and 2026. All eleven US labels examined describe delayed gastric emptying as potentially affecting the absorption of co-administered oral medications. Since the exenatide program, no study has evaluated a narrow therapeutic index victim across more than one administration schedule; the original warfarin and digoxin studies each used a single schedule. The omission may reflect an interaction paradigm built around enzymes and transporters. Current frameworks do not routinely trigger motility-specific studies because the standard in vitro screening cascade does not address gastric emptying. Total area under the concentration-time curve (AUC) may also fail to characterize rate-dependent effects in some victim drugs. Once a class warning is established, further study may receive less priority, and interactions managed by routine dose adjustment may go unreported. Of eleven US prescribing-information documents screened, six contributed quantitative data showing that the direction of effect is not uniform: thyroxine, atorvastatin and ramipril exposures have all been reported to increase under specific conditions, so a reduction in exposure should not be assumed. The class is also pharmacologically heterogeneous; ICH M12 places absorption-mediated interactions outside its scope, and the European Medicines Agency has adopted a concept paper proposing guidance covering them. I propose an evaluation framework built on biopharmaceutically stratified probe panels, timing- and titration-explicit designs, selective use of prespecified partial AUC endpoints for rate-sensitive victims, and physiologically based pharmacokinetic models qualified against human gastric emptying data.