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

May combine two claims.

The model underpredicted the metoprolol AUC and Cmax ratios with semaglutide; the simulated AUC ratio was 0.89 versus observed 1.19, and the simulated Cmax ratio was 0.95 versus reported 1.32.

“The exception to this concordance was metoprolol, where simulations under predicted the mean AUC and Cmax ratio when combined with semaglutide by 30% and 37%, respectively (Table 2).”

• Also stated in: § Discussion · plain

  “Notably, metoprolol exhibited the largest discrepancies, with the simulated AUC ratios underestimating the observed values (0.89 vs. 1.19). Additionally, Cmax predictions showed significant variability, particularly for metoprolol, where the simulated Cmax ratio (0.95) was markedly lower than the reported value (1.32).”

May combine two claims.

Tmax was strongly dependent on gastric emptying time, with minimal influence from small intestinal transit time; slower gastric emptying leads to a prolonged Tmax.

“Conversely, Tmax was strongly dependent on gastric emptying time, with minimal influence from small intestinal transit time (Figure 3D). The 3D surface plot illustrates that as gastric emptying time increased, Tmax was delayed, suggesting that time to peak concentration is primarily governed by the rate at which dabigatran leaves the stomach. Thus, slower gastric emptying leads to a prolonged Tmax”

• Also stated in: § Discussion · plain

  “Our sensitivity analyses showed that delays in gastric emptying result in a prolonged Tmax, which may impact the timing of peak drug concentrations and overall drug absorption.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the 2022 MEPS prescription drug survey, 6,072,000 individuals prescribed GLP-1RAs were identified; semaglutide was most common (54%), followed by dulaglutide (33%) and liraglutide (13%).

“In our analysis of the MEPS 2022 prescription drug survey, a total of 6,072,000 individuals prescribed GLP-1RAs were identified, with the most common GLP-1RAs prescribed being semaglutide (54%), followed by dulaglutide (33%) and liraglutide (13%) (Supplementary Table 3).2”

• cites [2] Medical Expenditure Panel Survey (MEPS). Content last reviewed July 2024. Agency for Healthcare Research and Quality, Rockville, MD. https://www.ahrq.gov/data/meps.html.Not checked yet

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May combine two claims.

AUC was primarily influenced by small intestinal transit time, with a positive correlation; gastric emptying time had only a minor effect on AUC.

“AUC was also primarily influenced by small intestinal transit time (Figure 3C). The 3D surface plot demonstrates a positive correlation between increasing small intestinal transit time and AUC, indicating that prolonged intestinal exposure significantly enhances overall drug absorption. In contrast, gastric emptying time had only a minor effect on AUC.”

• Also stated in: § Discussion · hedged

  “Given that small intestinal transit time was identified as a key determinant of AUC changes in our sensitivity analysis, future scintigraphy studies incorporating small intestinal motility assessments would provide additional clinical data to refine and validate these PBPK models.”

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Rivaroxaban did not exhibit significant changes in AUC, Tmax, or Cmax in the model, suggesting minimal interaction with GLP-1RA-induced motility delays.

“Rivaroxaban, which is primarily absorbed in the stomach, did not exhibit significant changes in AUC, Tmax, or Cmax, suggesting minimal interaction with GLP-1RA-induced motility delays.”

• AssumptionRests on an assumption: The GI motility effects observed with liraglutide are representative of GLP-1RA class effects for the purpose of the model.

May combine two claims.

Rosuvastatin and valsartan displayed only modest increases in Cmax compared to their AUC changes, whereas dabigatran showed a relatively larger Cmax increase.

“For instance, rosuvastatin and valsartan displayed only modest increases in Cmax compared to their AUC changes, whereas dabigatran showed a relatively larger Cmax increase.”

• AssumptionRests on an assumption: The GI motility effects observed with liraglutide are representative of GLP-1RA class effects for the purpose of the model.

May combine two claims.

Rosuvastatin and valsartan showed increased AUC without notable changes in Cmax.

“Other drugs, such as rosuvastatin and valsartan, showed increased AUC without notable changes in Cmax.”

• AssumptionRests on an assumption: The GI motility effects observed with liraglutide are representative of GLP-1RA class effects for the purpose of the model.

May combine two claims.

The Simcyp Simulator V23 demonstrated reasonable predictive accuracy for AUC ratios across most co-administered medications, but some simulated values deviated from the 90% confidence intervals in the semaglutide package insert.

“The Simcyp™ Simulator V23 demonstrated reasonable predictive accuracy for AUC ratios across most co-administered medications; however, some simulated values deviated from the 90% confidence intervals reported in the semaglutide package insert (Table 2).”

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Increases in gastric emptying time were associated with decreased Cmax, and reductions in small intestinal transit time also led to lower Cmax.

“Increases in gastric emptying time were associated with a decrease in Cmax, while reductions in small intestinal transit time also led to lower Cmax values.”

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In sensitivity analysis, the fraction of drug absorbed was primarily dependent on small intestinal transit time, with a positive correlation; gastric emptying time had no observable impact on the fraction absorbed.

“Local sensitivity analysis confirmed that the fraction of drug absorbed was primarily dependent on small intestinal transit time, as indicated by the positive correlation between small intestinal transit time and fraction absorbed (Figure 3A). In contrast, gastric emptying time had no observable impact on the fraction absorbed.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Capsule endoscopy does not replace radiolabeled scintigraphy, which remains the reference standard for measuring gastric emptying time.

“Another key limitation is that although capsule endoscopy allows for direct comparisons with orally administered solid dosage forms and provides complete lower GI transit times, it does not replace radiolabeled scintigraphy studies, which remain the reference standard for measuring gastric emptying time.17”

• cites [17] Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, McCallum RW, Nowak T, Nusynowitz ML, Parkman HP, Shreve P, Szarka LA, Snape WJ Jr, Ziessman HA; American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol. 2008 Mar; 103(3): 753– 63. doi: 10.1111/j.1572-0241.2007.01636.x. Epub 2007 Nov 19. 18028513 sourceNot checked yet

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Under GLP-1RA therapy, the recommended interval for sequestration-prone drugs like levothyroxine may need adjustment because delayed gastric emptying could alter drug binding dynamics and reduce absorption, potentially leading to therapeutic failure.

“However, under the influence of GLP-1RA therapy, this interval may need to be adjusted, as delayed gastric emptying could alter drug binding dynamics and further reduce absorption, potentially leading to therapeutic failure.”

• cites [16] AbbVie Inc. Synthroid® (Levothyroxine sodium tablets) [package insert]. North Chicago, IL: AbbVie Inc.; 2023.Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

PBPK models generally achieve AUC ratio predictions within 20% to 50% error for well-characterized drug-drug interactions.

“For reference, PBPK models generally achieve AUC ratio predictions within 20% to 50% error for well-characterized DDIs.12”

• cites [12] Hanke N, Frechen S, Moj D, Britz H, Eissing T, Wendl T, Lehr T. PBPK Models for CYP3A4 and P-gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin. CPT Pharmacometrics Syst Pharmacol. 2018 Oct; 7(10): 647– 659. doi: 10.1002/psp4.12343. Epub 2018 Sep 7. 30091221 PMC6202474 sourceNot checked yet

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Apixaban, which is absorbed in the distal small intestine and colon, may be more vulnerable to prolonged transit times, potentially increasing drug accumulation and bleeding risk.

“In contrast, apixaban, which is absorbed in the distal small intestine and colon, may be more vulnerable to prolonged transit times, potentially increasing drug accumulation and bleeding risk.15”

• cites [15] Byon W, Nepal S, Schuster AE, Shenker A, Frost CE. Regional Gastrointestinal Absorption of Apixaban in Healthy Subjects. J Clin Pharmacol. 2018 Jul; 58(7): 965– 971. doi: 10.1002/jcph.1097. Epub 2018 Mar 26. 29578609 sourceNot checked yet

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Both delayed gastric emptying and faster small intestinal transit contribute to a reduction in peak plasma concentrations.

“This suggests that both delayed gastric emptying and faster small intestinal transit contribute to a reduction in peak plasma concentrations, highlighting a dynamic interplay between gastric and intestinal motility in determining Cmax.”

May combine two claims.

Conflicting findings exist for effects of semaglutide and tirzepatide on ethinyl estradiol exposure; tirzepatide lowered AUC by 21% whereas semaglutide increased by similar fraction.

“For example, tirzepatide lowered the area under the curve (AUC) of ethinyl estradiol by 21% whereas semaglutide increased the AUC by a similar fraction.4,5”

• cites [4] Eli Lilly and Company. Mounjaro® (tirzepatide) injection [package insert]. Indianapolis, IN: Eli Lilly and Company; 2022.Not checked yet

  Not checked in the free run.

• cites [5] Nordisk Novo. Ozempic® (semaglutide) injection [package insert]. Plainsboro, NJ: Novo Nordisk; 2023.Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The model has inherent limitations related to built-in physiological assumptions, including a constant GLP-1RA effect on gastric motility, without accounting for tachyphylaxis.

“Our model also has inherent limitations related to built-in physiological assumptions, including a constant GLP-1RA effect on gastric motility, without accounting for tachyphylaxis.”

• AssumptionThe authors state this as an assumption: The model assumes a constant GLP-1RA effect on gastric motility and does not account for tachyphylaxis.

Probably not a substantial claim: may not pass S3 (load-bearing).

Current guidelines for drugs with sequestration potential, such as levothyroxine, recommend taking them at least 4 hours apart from interfering agents.

“For instance, current guidelines for drugs with sequestration potential, such as levothyroxine, recommend taking them at least 4 hours apart from interfering agents like phosphate binders or multivitamins to prevent reduced drug absorption.16”

• cites [16] AbbVie Inc. Synthroid® (Levothyroxine sodium tablets) [package insert]. North Chicago, IL: AbbVie Inc.; 2023.Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The potential for diminishing effects on gastric motility over time remains largely unexplored and may influence long-term drug absorption patterns.

“The potential for diminishing effects on gastric motility over time remains largely unexplored and may influence long-term drug absorption patterns.”

• AssumptionThe authors state this as an assumption: The model assumes a constant GLP-1RA effect on gastric motility and does not account for tachyphylaxis.

May combine two claims.

The capsule endoscopy measurements used in this model were obtained from patients with diabetes mellitus, some with documented gastroparesis, but did not include patients with obesity.

“Additionally, the capsule endoscopy measurements used in this model were obtained from patients with diabetes mellitus, some of whom had documented gastroparesis, but did not include patients with obesity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

GLP-1RAs have been shown to reduce gastric acid secretion, with some studies reporting up to a 20% increase in gastric pH.

“GLP-1RAs have been shown to reduce gastric acid secretion, with some studies reporting up to a 20% increase in gastric pH.19”

• cites [19] Quast DR, Schenker N, Menge BA, Nauck MA, Kapitza C, Meier JJ. Effects of Lixisenatide Versus Liraglutide (Short- and Long-Acting GLP-1 Receptor Agonists) on Esophageal and Gastric Function in Patients With Type 2 Diabetes. Diabetes Care. 2020 Sep; 43(9): 2137– 2145. doi: 10.2337/dc20-0720. Epub 2020 Jul 9. 32647054 sourceNot checked yet

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May combine two claims.

If diabetes, obesity, and GLP-1RA effects on gastric motility are additive, the model may underestimate GLP-1RA-associated gastric hypomotility's impact; if redundant, it may overestimate.

“If these effects are found to be additive, the model may underestimate GLP-1RA-associated gastric hypomotility’s impact on oral drug absorption; conversely, if they are redundant, the model may overestimate these effects.”

• AssumptionThe authors state this as an assumption: The model assumes that diabetes, obesity, and GLP-1RA therapy have independent effects on gastric motility.

May combine two claims.

Existing research on how GLP-1RAs affect absorption of oral medications is limited but indicates potential impacts on Cmax, AUC, and Tmax of coadministered oral drugs.

“The existing research on how GLP-1RAs affect the absorption of oral medications is limited but indicates potential impacts on maximum concentration (Cmax), total drug exposure defined by AUC, and time to Cmax (Tmax) of coadministered oral drugs.6”

• cites [6] Calvarysky B, Dotan I, Shepshelovich D, Leader A, Cohen TD. Drug-Drug Interactions Between Glucagon-Like Peptide 1 Receptor Agonists and Oral Medications: A Systematic Review. Drug Saf. 2024; 47(5). doi: 10.1007/s40264-023-01392-3 PMC11018670 38273155 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

This pH shift could alter the solubility and absorption of oral medications and may have synergistic effects when combined with other pH-altering drugs.

“This pH shift could alter the solubility and absorption of oral medications and may have synergistic effects when combined with other pH-altering drugs, such as proton pump inhibitors and H2 receptor antagonists.”

May combine two claims.

PBPK modeling has emerged as an alternative, non-invasive method for assessing DDI potential and is often used as a surrogate for clinical trials.

“Physiologically-based pharmacokinetic (PBPK) modeling has emerged as an alternative, non-invasive method for assessing DDI potential and is often used as a surrogate for clinical trials.7”

• cites [7] FDA. Drug-Drug Interaction Assessment for Therapeutic Proteins | Guidance for Industry. Published online 2023. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugsand/orNot checked yet

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May combine two claims.

The Tmax shift combined with relatively smaller increases in Cmax suggests that while peak concentrations were delayed, their magnitudes did not increase as dramatically.

“This Tmax shift, combined with the relatively smaller increases in Cmax, suggests that while peak concentrations were delayed, their magnitudes did not increase as dramatically.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The model did not incorporate the effects of GLP-1RA therapy on gastric pH.

“Lastly, our model did not incorporate the effects of GLP-1RA therapy on gastric pH.”

May combine two claims.

The increased systemic exposure of certain drugs may not always lead to toxicity, but remains a concern for high-risk medications such as direct oral anticoagulants.

“Although the increased systemic exposure of certain drugs may not always lead to toxicity, it remains a concern for high-risk medications such as direct oral anticoagulants.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A validated substrate profile was not available for apixaban in Simcyp V23 to test this potential.

“A validated substrate profile was not available for apixaban in Simcyp™ V23 to test this potential.”