Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

Buckley, Stephen T.; Bækdal, Tine A.; Vegge, Andreas; Maarbjerg, Stine; Pyke, Charles; Ahnfelt-Rønne, Jonas; Madsen, Klavs; Schéele, Susanne G.; Alanentalo, Tomas; Kirk, Rikke Kaae; Pedersen, Betty Lomstein; Skyggebjerg, Rikke Bjerring; Benie, Andrew J.; Strauss, Holger M.; Wahlund, Per-Olof; Bjerregaard, Simon; Farkas, Erzsébet; Fekete, Csaba; Søndergaard, Flemming L.; Borregaard, Jeanett; Hartoft‐Nielsen, Marie‐Louise; Knudsen, Lotte Bjerre

doi:10.1126/scitranslmed.aar7047

Cited by 347 publications

(359 citation statements)

References 38 publications

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“…Semaglutide (Novo Nordisk, Denmark) is a long‐acting human GLP‐1 analogue, which can be administered once weekly subcutaneously (s.c.), or once daily orally when co‐formulated with the absorption enhancer sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate (commonly known as ‘SNAC’) . The half‐life (~7 days) and clinical effects of semaglutide are similar irrespective of mode of administration .…”

Section: Introductionmentioning

confidence: 99%

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

125

106

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Aim To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient‐level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P‐values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon‐like peptide‐1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

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Section: Introductionmentioning

confidence: 99%

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

125

106

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“…The low intestinal permeability of most peptides is related to their large size, low lipophilicity, and extensive hydrogen binding, all of which are physicochemical properties that predict low passive membrane transport [39]. A strategy to circumvent low intestinal permeability was recently approved for the first time in an oral product, for which a PE increased the intestinal membrane transport of semaglutide, a pharmaceutical peptide containing 31 amino acids, even though the bioavailability in dog is as low as 0.29% of the oral dose (data from patent: wo2012080471) [6]. The use of PEs has also been proposed in the colon, as the low luminal volumes and long transit time allow for high local mucosal PE concentrations at extended exposure times.…”

Section: Discussionmentioning

confidence: 99%

“…The rat SPIP model may also be used to investigate regional intestinal differences in how pharmaceutical excipient(s) affect drug permeation and overall absorption rate. This is especially relevant because of the renewed interest in permeation enhancers (PE), also called absorption-modifying excipients (AME), for enabling oral administration of low-permeation compounds, for example, peptides [6,7]. Some advocates of this formulation approach propose the colon as a potential target for PEs, because the colon has a longer residence time, its mucosa may be more easily affected, and it does not have the higher peptidase activity of the upper GI tract [8,9].However, few comparisons of the small and large intestine in rat have been made on the direct permeability effects of PEs in the same laboratory.…”

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confidence: 99%

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

et al. 2020

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Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.Pharmaceutics 2020, 12, 242 2 of 14 frequently used in pharmaceutical development to evaluate the potential success of a drug, for instance with oral modified-release (MR) dosage forms. In MR dosage forms, the drug is released throughout the gastrointestinal (GI) tract prior to absorption so the regional intestinal permeability needs to be sufficiently high in both the small and large intestine. The rat and human small intestine have similar drug intestinal absorption profiles and transporter expression patterns, but differ in their enzymatic metabolism [2]. Differences in absorption from the rat and human colon have not been extensively compared, but a recent meta-analysis of rat SPIP data reports regional differences in drug permeability for 42 drugs in this species [3].How relevant for humans are the regional intestinal drug permeability values determined in the rat SPIP model? It is difficult to answer this because of the limited amount of human reference permeability data from the lower GI trac...

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“…In September 2019, oral semaglutide became the first orally administered GLP-1 receptor agonist to be approved by the FDA 2 . Oral semaglutide uses an absorption enhancer, sodium N-(8- [2-hydroxybenzoyl] amino) caprylate, to facilitate absorption across the gastric mucosa, and aims to provide the benefits of existing GLP-1 receptor agonists without the requirement for daily or weekly injection 3 . Patients are required to take oral semaglutide at least 30 min before the first food, beverage, or other oral medications of the day with no more than 4 ounces of water only.…”

Section: Introductionmentioning

confidence: 99%

Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis

Hansen

Nuhoho

Ali

et al. 2020

Journal of Medical Economics

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Aims:The efficacy and safety of oral semaglutide, the first glucagon-like peptide-1 (GLP-1) receptor agonist developed for oral administration for the treatment of type 2 diabetes, was evaluated in the PIONEER clinical trial program, and a recently published network meta-analysis allowed comparison with further injectable GLP-1 receptor agonists. The present study aimed to assess the short-term costeffectiveness of oral semaglutide 14 mg versus subcutaneous once-weekly dulaglutide 1.5 mg, onceweekly exenatide 2 mg, twice-daily exenatide 10 mg, once-daily liraglutide 1.8 mg, once-daily lixisenatide 20 mg, and once-weekly semaglutide 1 mg, in terms of the cost per patient achieving glycated hemoglobin (HbA1c) targets (cost of control). Materials and methods: Cost of control was calculated by dividing the annual treatment costs associated with an intervention by the proportion of patients achieving the treatment target with an intervention, with outcomes calculated for targets of HbA1c 6.5% and HbA1c <7.0% for all included GLP-1 receptor agonists. Annual treatment costs were accounted in 2019 United States dollars (USD), based on 2019 wholesale acquisition cost. Results: For the treatment target of HbA1c 6.5%, once-weekly semaglutide 1 mg and oral semaglutide 14 mg were associated with the lowest costs of control, at USD 15,430 and USD 17,383 per patient achieving target, respectively. Similarly, the cost of control was lowest with once-weekly semaglutide 1 mg at USD 12,627 per patient achieving target, followed by oral semaglutide 14 mg at USD 13,493 per patient achieving target for the target of HbA1c <7.0%. All other interventions were associated with higher cost of control values for both targets. Conclusions: Oral semaglutide 14 mg is likely to be cost-effective versus dulaglutide, exenatide (once weekly and twice daily), liraglutide, and lixisenatide in terms of bringing people with type 2 diabetes to glycemic control targets of HbA1c 6.5% and HbA1c <7.0% in the US. ARTICLE HISTORY

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Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

Cited by 347 publications

References 38 publications

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis

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