Reference
Buckley, S. T., Bækdal, T. A., Vegge, A., Maarbjerg, S. J., Pyke, C., Ahnfelt-Rønne, J., Madsen, K. G., Schéele, S. G., Alanentalo, T., Kirk, R. K., Pedersen, B. L., Skyggebjerg, R. B., Benie, A. J., Strauss, H. M., Wahlund, P.-O., Bjerregaard, S., Farkas, E., Fekete, C., Søndergaard, F. L., … Knudsen, L. B. (2018). Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Science Translational Medicine, 10(467), eaar7047. https://doi.org/10.1126/scitranslmed.aar7047
Info
FirstAuthor:: Buckley, Stephen T.
Author:: Bækdal, Tine A.
Author:: Vegge, Andreas
Author:: Maarbjerg, Stine J.
Author:: Pyke, Charles
Author:: Ahnfelt-Rønne, Jonas
Author:: Madsen, Kim G.
Author:: Schéele, Susanne G.
Author:: Alanentalo, Tomas
Author:: Kirk, Rikke K.
Author:: Pedersen, Betty L.
Author:: Skyggebjerg, Rikke B.
Author:: Benie, Andrew J.
Author:: Strauss, Holger M.
Author:: Wahlund, Per-Olof
Author:: Bjerregaard, Simon
Author:: Farkas, Erzsébet
Author:: Fekete, Csaba
Author:: Søndergaard, Flemming L.
Author:: Borregaard, Jeanett
Author:: Hartoft-Nielsen, Marie-Louise
Author:: Knudsen, Lotte Bjerre
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Title:: Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist
Year:: 2018
Citekey:: BuckleyEtAl_2018_TranscellularStomachAbsorption
itemType:: journalArticle
Journal:: Science Translational Medicine
Volume:: 10
Issue:: 467
Pages:: eaar7047
DOI:: 10.1126/scitranslmed.aar7047
Link
Abstract
An orally delivered GLP-1 analog coformulated with the absorption enhancer SNAC achieves transcellular-directed absorption in the stomach.
Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.
Yellow: Interesting
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Despite the remarkable pharmacological effects of simultaneous glucose, body weight, and blood pressure lowering and cardiovascular risk reduction already achieved with semaglutide administered subcutaneously, the mode of administration is likely a barrier for some potential users. This barrier could be overcome with the availability of an oral formulation of semaglutide.
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many peptides obtain protraction from the subcutaneous administration site while having a shorter intravenous t1⁄2, making the duration of action unsuitably short if given orally.
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semaglutide molecule well suited for oral delivery when coformulated with an absorption enhancer, which can sufficiently augment its absorption. Moreover, once-daily administration of a compound with a t1⁄2 of ~1 week will have a favorable effect on intraindividual variability in exposure.
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we report a detailed mechanistic examination into the absorption of semaglutide after oral administration when coformulated with the absorption enhancer, sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC).
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complete tablet erosion (CTE) was observed to occur in the stomach of all evaluable human individuals (mean time to CTE, 57 min).
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To definitively demonstrate the prevailing role of the stomach in the absorption of oral semaglutide, we measured semaglutide plasma concentrations in the splenic vein (vena lienalis; draining the gastric cavity) and in the portal vein (vena porta; draining the gastrointestinal system) after intragastric dosing in nonligated dogs. Concentrations were higher in the splenic vein over the first 30 min after dosing, as reflected by a ratio of the area under the curve (AUC0–30min) between the splenic and portal veins of 1.94 [95% confidence interval (CI), 1.15 to 2.74; P < 0.05; Fig. 1F], confirming the stomach as the predominant site of absorption.
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To establish the concentration of SNAC necessary to confer therapeutically relevant plasma exposure of semaglutide, we administered a single dose of oral semaglutide (5 mg) with either 150 or 300 mg of SNAC to healthy individuals
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Semaglutide plasma concentrations were higher when semaglutide was coformulated with 300 mg of SNAC (Fig. 2A), whereas higher amounts (600 mg) led to lower semaglutide plasma concentrations (fig. S4). These results suggest that 300 mg represents an appropriate amount of SNAC to enhance absorption of semaglutide in this formulation, potentially by avoiding salting out effects and precipitation, which may be associated with higher amounts of SNAC.
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A significant ~7-fold increase in the apparent permeability (Papp) of semaglutide was seen with 80 mM SNAC versus control
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Further corroborating the localized nature of semaglutide absorption, the immunoreactivity of semaglutide in stomach tissue was restricted to epithelial surfaces immediately under and around the site of tablet identification
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AUC0–180min was significantly lower for liraglutide compared to semaglutide (P = 0.002; Fig. 3A). The SNAC orthoisomer, o-SNAC, showed a markedly diminished absorption-enhancing effect compared to SNAC (Fig. 3, B and C, and fig. S5).
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Exposure to SNAC substantially increased the intracellular accumulation of semaglutide compared to control cells (P < 0.001; Fig. 3D).
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SNAC promotes monomerization of semaglutide Fatty acid–acylated GLP-1 analogs are known to form oligomers (13), which could affect absorption. We examined the effect of SNAC on semaglutide self-association using three orthogonal biophysical characterization techniques:
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Increasing the concentration of SNAC at a constant concentration of semaglutide resulted in a decrease in the apparent molecular mass, which is consistent with a shift in the oligomeric state of semaglutide toward its monomeric form
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SNAC augmented the pH of SGF from acidic to neutral within 5 to 15 min (Fig. 3M)
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The primary digestive enzyme in the stomach is pepsin. Optimal pepsin activity is observed at low pH, such as that found in gastric fluid of the stomach (pH 2 to 4) (14). Given the peptide character of semaglutide, it is reasonable to expect that pepsin may degrade semaglutide in the stomach. However, in light of the pronounced buffering effect of SNAC, the impact of pH on semaglutide stability was examined in the presence of pepsin
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the effect of pepsin on semaglutide stability was most profound at low pH, with semaglutide being most labile toward pepsin at pH 2.6 (t1⁄2 = 16 min; Fig. 3N). In contrast, increasing the pH to 5.0 extended the t1⁄2 of semaglutide to 34 min, and at neutral pH
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o provide a deeper insight into the behavior of semaglutide at the absorptive site in the stomach, we used immunofluorescence imaging on canine gastric tissue. After dosing, intense immunoreactivity for semaglutide was confined to the region in and around the site of tablet identification, whereas semaglutide staining was conspicuous
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reactivity was mostly restricted to the surface mucous epithelial cell layer in the pit and neck regions of the gastric mucosa
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Semaglutide was detected within blood vessels of the lamina propria mucosae 5 min after dosing
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Red: Disagree with the paper
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all individuals dosed in the fasted state had measurable semaglutide exposure (Fig. 1D, fasting state), emphasizing that absorption of oral semaglutide in the stomach is hindered by the presence of food, and thus, administration of oral semaglutide should be in the fasting state