Pharmacokinetics and Pharmacodynamics of Exenatide Extended-Release After Single and Multiple Dosing

Fineman, Mark; Flanagan, Shawn D.; Taylor, Kristin; Aisporna, Maria; Shen, Larry Z.; Mace, Kenneth F.; Walsh, B. Timothy; Diamant, Michaëla; Cirincione, Brenda; Kothare, Prajakti A.; Li, Wen-I; MacConell, Leigh

doi:10.2165/11585880-000000000-00000

Cited by 123 publications

(150 citation statements)

References 21 publications

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“…Weekly exenatide administration led to clinically significant improvements in glycaemic control that were evident by week 4, and steady‐state concentration of exenatide at approximately week 8 was consistent with previous studies 16, 17, 18, 19. Continuous exposure of exenatide translated into similar glucose‐lowering effects at the beginning and end of the week.…”

Section: Discussionsupporting

confidence: 87%

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Frías

Nakhle²,

Ruggles

et al. 2016

Diabetes Obesity Metabolism

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AimTo assess the effects of once‐weekly exenatide on 24‐hour glucose control and variability.Materials and methodsThis double‐blind, placebo‐controlled trial randomized metformin‐treated adults with type 2 diabetes to once‐weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM‐measured 24‐hour mean glucose level.ResultsIn the once‐weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention‐to‐treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once‐weekly exenatide significantly (p < 0.001) reduced 24‐hour mean glucose level versus placebo (week 4, −1.44 vs −0.29 mmol/L; week 10, −1.71 vs −0.17 mmol/L), with consistent control throughout the week. Once‐weekly exenatide significantly reduced FPG and 2‐hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, −1.65 vs −0.11 mmol/L; PPG, −1.79 vs −0.11 mmol/L) and week 10 (FPG, −2.32 vs −0.28 mmol/L; PPG, −2.46 vs −0.33 mmol/L). At week 10, once‐weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; −0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (−0.35 vs 0.04 mmol/L). By week 10, once‐weekly exenatide‐treated participants spent more time in euglycaemia (once‐weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection‐site nodule (once‐weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%).ConclusionsIn metformin‐treated participants with type 2 diabetes, once‐weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24‐hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

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Section: Discussionsupporting

confidence: 87%

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Frías

Nakhle²,

Ruggles

et al. 2016

Diabetes Obesity Metabolism

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“…36). As expected, blood glucose levels were reduced by Ex-4 within 24 hours and remained lower during the subsequent treatment period ( Figure 2C and Supplemental Figure 2E).…”

Section: Introductionsupporting

confidence: 80%

“…10, 31-35). The circulating Ex-4 level in our system (~4 ng/ml) was much higher than the basal plasma GLP-1 level in mice (48,49) or healthy humans (50) but close to the therapeutic concentration target for GLP-1R agonists in clinical use (36). The duration of Ex-4 infusion in our study was shorter (28 days) Table 1 for the quantification of TUNEL + β cells in PBS+saline-treated, Ex-4+saline-treated, PBS+FK506-treated, and Ex-4+FK506-treated graft samples from 3 juvenile donors.…”

Section: Discussionmentioning

confidence: 65%

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

Dai

Hang

Shostak

et al. 2017

Journal of Clinical Investigation

127

143

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“…S1, A and B, respectively; Supplemental Material for this article can be found on the AJPEndocrinology and Metabolism web site). The mean exenatide plasma concentration at the termination of this study was 166 Ϯ 24 pg/ml and was in the range of concentrations found in patients dosed with exenatide (20,25). Additionally, 7.2 nmol·kg Ϫ1 ·day Ϫ1 of exenatide significantly decreased Hb A 1c , plasma glucose, and body weight in HF-STZ mice compared Acute effects of exenatide on amylase and lipase during chemically induced pancreatitis in normal or diabetic rats or diabetic mice.…”

Section: Effect Of Single-dose or Subchronic Administration Of Exenatmentioning

confidence: 54%

“…Cytokine concentrations were calculated using the four-parameter logistic standard curve fit method (SoftMax Pro; Molecular Devices, Sunnyvale, CA). Plasma exenatide concentrations were measured using an immunoenzymetric assay developed at Amylin Pharmaceuticals, as described previously (20).…”

Section: Methodsmentioning

confidence: 99%

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

Tatarkiewicz

Smith

Sablan

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg Ϫ1 ·day Ϫ1 ) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1␤, IL-2, IL-6, MCP-1, IFN␥, and TNF␣) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN-or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents. diabetes; mouse; rat; caerulein; sodium taurocholate; pancreatic duct GLUCAGON-LIKE PEPTIDE-1 (GLP-1) exerts multiple glucoregulatory actions by enhancing glucose-dependent insulin secretion, regulating gastric emptying, decreasing postprandial glucagon secretion, and decreasing food intake. Moreover, GLP-1 has been observed to improve ␤-cell mass by augmenting ␤-cell survival and proliferation in rodents (7,19,42). In recent years, the therapeutic potential of GLP-1 receptor (GLP-1R) agonists or dipeptidyl peptidase IV (DPP IV) inhibitors for treatment of type 2 diabetes gained widespread attention, and several drugs affecting the GLP-1 pathway were approved to control hyperglycemia, including the GLP-1R agonists exenatide and liraglutide (12, 18) and the DPP IV inhibitors sitagliptin and saxagliptin.Cases of pancreatitis have been observed in patients treated with GLP-1 receptor agonists and DPP IV inhibitors (1, 9, 10, 13, 38). Acute pancreatitis is a complex clinical condition that ranges in severity from mild to life-threatening. Abdominal pain, ultrasound-confirmed pancreatic pathological changes and increased plasma amylase and lipase concentrations are the most common markers of acute pancreatitis in the clinic (21). Type 2 diabetes and/or obesity are risk factors for the development of pa...

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Pharmacokinetics and Pharmacodynamics of Exenatide Extended-Release After Single and Multiple Dosing

Cited by 123 publications

References 21 publications

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

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