GLP‐1RA‐induced delays in gastrointestinal motility: Predicted effects on coadministered drug absorption by PBPK analysis

Feb 24, 2025Pharmacotherapy

How GLP-1RA slows digestion may affect absorption of other drugs, predicted by computer modeling

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Abstract

GLP-1RA-induced gastric emptying delays resulted in a 205% increase in the area under the concentration-time curve () for dabigatran.

Increased AUC and prolonged time to maximum concentration (Tmax) were observed for several medications due to GLP-1RA-related gastric emptying delays.
Rosuvastatin and valsartan showed increases in AUC by 64% and 90%, respectively.
Dabigatran, a medication with a narrow therapeutic index, exhibited the most significant changes in pharmacokinetics.
The findings indicate potential clinical relevance for drug-drug interactions (DDIs) with oral medications when GLP-1RAs are used.

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BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.

OBJECTIVES: This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.

METHODS: Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran.

RESULTS: GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve () and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure.

CONCLUSIONS: suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.

Key numbers

205%

Increase in for Dabigatran

Increase in area under the concentration-time curve for dabigatran due to effects.

64%

Increase in for Rosuvastatin

Increase in area under the concentration-time curve for rosuvastatin due to effects.

90%

Increase in for Valsartan

Increase in area under the concentration-time curve for valsartan due to effects.

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GLP‐1RA‐induced delays in gastrointestinal motility: Predicted effects on coadministered drug absorption by PBPK analysis

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