163: GLP-1-Induced Delays in GI Motility & Their Effects on Co-Administered Drug Absorption: A PBPK Analysis

Statement of Purpose, Innovation or Hypothesis: With the FDA's approval of glucagon-like peptide-1 (GLP-1) receptor agonists as a treatment for obesity, their use has surged across the United States amid rising obesity rates. Despite GLP-1 agonists not typically causing drug-drug interactions through cytochrome or transporter mechanisms, their impact on gastrointestinal (GI) motility could alter the pharmacokinetics of concurrent medications in patients with obesity. This research aims to fill the gap in understanding these potential interactions by assessing the pharmacokinetic profiles of commonly used comedications in the presence of GLP-1-induced delays in GI motility, utilizing physiological-based pharmacokinetic (PBPK) modeling and simulation.

Description of Methods & Materials: Utilizing Certara's Simcyp® Simulator V23 we performed PBPK modeling and simulation to examine the impact of GLP-1-associated delays in GI motility on the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin. These drugs were selected based on the availability of pharmacokinetic data and established PBPK models in Simcyp’s compound repository. GLP-1-associated delays in gastric emptying and small intestine motility were incorporated by modifying model GI mean residence time parameters, using capsule endoscopy measurements in patients taking semaglutide and liraglutide.^1,2 Simulations were performed on a virtual cohort of obese adults (n=100), comparing the pharmacokinetic parameter ratios of AUC and C_max to clinical data in adults on semaglutide.3 Additionally, an exploratory analysis was conducted on medications identified as being frequently co-administered with GLP-1 agonists based on responses from the 2021 Medical Expenditure Panel Survey (MEPS). This analysis included rosuvastatin, valsartan, rivaroxaban, bupropion, and dabigatran, assessing their AUC_0-24h, C_max, and T_max after a single dose during peak GLP-1-induced GI delays.

Data & Results: The Simcyp® Simulator V23 effectively predicted the pharmacokinetic exposure ratios of the selected compounds, with most predictions aligning within the 95% confidence interval of the observed semaglutide data (Table 1). In the exploratory analysis of medications identified from the MEPS, the model predicted that peak GLP-1 delays increased the area under the curve (AUC_0-24h) for rosuvastatin, valsartan and dabigatran by 65-, 82- and 132%, respectively (Figure 1). Additionally, these medications showed delayed T_max and, to a lesser extent, increased C_max.

Interpretation, Conclusion or Significance: PBPK models, as demonstrated with Certara's Simcyp® Simulator V23, are valuable exploratory tools to gain insights into potential drug-drug interactions. Among the 10 drugs included in this analysis, 7 are not predicted to have clinically significant PK alterations. While this model requires further validation against clinical data, our findings highlight the potential for GLP-1-induced delays in GI motility to alter drug exposure metrics like AUC, C_max and T_max. Specifically, the potential effects of GLP-1 agonists on the narrow therapeutic index anticoagulant, dabigatran deserve further clinical exploration to rule out a risk for a major drug-drug interaction.

Disclosures:

Citations/References: 1. Nakatani Y, Maeda M, Matsumura M, Shimizu R, Banba N, Aso Y, Yasu T, Harasawa H. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. Diabetes Metab. 2017 Oct;43(5):430-437. doi: 10.1016/j.diabet.2017.05.009. Epub 2017 Jun 23. PMID: 28648835. 2. Mojca Jensterle, Simona Ferjan, Luka Lezaic, Aljaz Socan, Katja Zaletel, Prof Andrej Janez, RF24 | PSUN116 Once-weekly semaglutide delays a late phase gastric emptying of solid meal measured by repeated scintigraphic imaging in obese women with PCOS, Journal of the Endocrine Society, Volume 6, Issue Supplement_1, November-December 2022, Pages A33–A34, https://doi.org/10.1210/jendso/bvac150.070. 3. Semgatludie [Package Insert], Bagsværd, Denmark, Novo Nordisk;12/2017.

Additional Information/Authors: N/A